Molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy

@article{Parano1996MolecularBO,
  title={Molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy},
  author={Enrico Parano and Lorenzo Pavone and Raffaele Falsaperla and R R Trifiletti and C Wang},
  journal={Annals of Neurology},
  year={1996},
  volume={40}
}
We report on a family with childhood‐onset spinal muscular atrophy with intrafamilial phenotypic variation. Typical of a large majority of such patients, both the child with spinal muscular atrophy type I and the child with type II were missing both copies of the survival motor neuron telomeric gene (SMNT). The more severely affected child, however, showed genotypic evidence consistent with the de novo loss of DNA sequence in addition to that inherited by both affected children. These data… 
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References

SHOWING 1-10 OF 24 REFERENCES
Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy.
TLDR
The frequency of deletions in a recently characterised candidate survival motor neuron (SMN) gene are analysed and show that this gene is disrupted by deletion in SMA patients, confirming previous analyses and implications for the identification of the gene or genes causing the disease.
Genetic mapping of chronic childhood-onset spinal muscular atrophy to chromosome 5q1 1.2–13.3
TLDR
Analysis of 13 clinically heterogeneous SMA families finds that 'chronic' childhood-onset SMA (including intermediate SMA or SMA type II, and Kugelberg–Welander or S MA type III) is genetically homogeneous, mapping to chromosomal region 5ql 1.3.
Intrafamilial heterogeneity in hereditary motor neuron disease
TLDR
The intrafamilial variation of phenotype suggests a similar pathogenesis for some of the varied types of familial MND and the need for careful inquiry of family history in all patients with MND.
De novo and inherited deletions of the 5q13 region in spinal muscular atrophies.
TLDR
Results indicate that deletion events are statistically associated with the severe form of spinal muscular atrophy.
Phenotypic heterogeneity of spinal muscular atrophy mapping to chromosome 5q11.2‐13.3 (SMA 5q)
TLDR
Analysis of SMA 5q families supports the view that, with certain exceptions, there is little phenotypic intrafamilial variability and there are as yet no unambiguous cases of typical SMA families that are clearly unlinked to the locus at 5q–ie, no clear cases of nonallelic heterogeneity.
Genetic homogeneity between acute and chronic forms of spinal muscular atrophy
THE childhood-onset spinal muscular atrophies (SMAs) describe a heterogeneous group of disorders that selectively affect the alpha motoneuron. We have shown that chronic childhood-onset SMA (SMA II
Gene for chronic proximal spinal muscular atrophies maps to chromosome 5q
TLDR
A genetic linkage analysis of the chronic forms of spinal muscular atrophies found no evidence for genetic heterogeneity was found for types II and III in this study, suggesting that these two forms are allelic disorders.
Molecular analysis of candidate genes on chromosome 5q13 in autosomal recessive spinal muscular atrophy: evidence of homozygous deletions of the SMN gene in unaffected individuals.
TLDR
The occurrence of SMN deletions in unaffected individuals suggests that other genes or mechanisms may be necessary to produce the SMA phenotype, and the largest divergence between age at onset of an affected subject and the present age of unaffected deleted sibs is four decades now.
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