Molecular basis of phenotypic heterogeneity in siblings with spinal muscular atrophy

  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},
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… 
Maternal mosaicism for a second mutational event in a type I spinal muscular atrophy family.
A type I SMA family is presented in which a mutant SMA chromosome has undergone a second mutation event, and the occurrence of three affected siblings harboring this same mutation in one generation of this family indicates the existence of maternal germ-line mosaicism for cells carrying the second mutation.
Phenotypic variability in siblings with type III spinal muscular atrophy
Two brothers are described who illustrate the increasing importance of molecular genetics in investigating patients with neuromuscular diseases and highlight the increasing need to understand the mechanisms behind SMA's phenotypic variability.
Clinical and molecular diagnosis of spinal muscular atrophy.
The objective is to stress the variability in the clinical features and recent advances in the molecular diagnosis for SMA.
Molecular Basis of Genetic Heterogeneity: Role of the Clinical Neurologist
  • L. Rowland
  • Medicine, Psychology
    Journal of child neurology
  • 1998
Advances in molecular genetics have transformed the clinical neurology of heritable diseases and provide clinicians with new responsibilities and opportunities in defining clinical syndromes and influencing the evolution of the authors' clinical language.
Spinal muscular atrophy due to an isolated deletion of exon 8 of the telomeric survival motor neuron gene
Evidence is provided that an isolated deletion of SMNT exon 8 is associated with the milder subtypes of SMA, and that the additional deletion of the NAIP gene exacerbates the severity of the disease.
Molecular Mechanisms of Spinal Muscular Atrophy
  • C. Sumner
  • Biology
    Journal of child neurology
  • 2007
Progress has been made in developing therapeutic strategies targeted to specific points along the pathogenetic pathway of spinal muscular atrophy, and Histone deacetylase inhibitors will be discussed as an example.
A population‐based study of genotypic and phenotypic variability in children with spinal muscular atrophy
Aims: To describe the occurrence of spinal muscular atrophy (SMA) in childhood; to evaluate if any of the genes in the SMA region on chromosome 5q13 correlates with disease severity; to make
Spinal Muscular Atrophy (SMA) Subtype Concordance in Siblings: Findings From the Cure SMA Cohort
These findings show that most siblings with SMA shared the same subtype concordance (most commonly Type I), enabling better individual treatment and management planning in view of new treatment options and newborn screening initiatives.
Therapeutics development for spinal muscular atrophy


Deletions in the survival motor neuron gene on 5q13 in autosomal recessive spinal muscular atrophy.
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
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
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.
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)
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
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.
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.