A dominantly inherited lower motor neuron disorder presenting at birth with associated arthrogryposis.

Fleury, P; Hageman, G.

doi:10.1136/jnnp.48.10.1037

Cited by 71 publications

(61 citation statements)

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“…Lower extremity predominance has been described in several other dominant SMA families, [25][26][27] including the one family with a mutation in TRPV4 on 12q23-q24. 15,16,28,29 However, in contrast to SMA-LED, these pedigrees showed more prominent distal leg weakness, high rates of arthrogryposis, and congenital onset. Although the features of SMA-LED are different from most other autosomal dominant SMAs, we cannot exclude the possibility that SMA-LED represents one end of a spectrum shared with these other families.…”

Section: Clinical Featuresmentioning

confidence: 80%

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Dominant spinal muscular atrophy with lower extremity predominance

et al. 2010

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Objective: Spinal muscular atrophies (SMAs) are hereditary disorders characterized by weakness from degeneration of spinal motor neurons. Although most SMA cases with proximal weakness are recessively inherited, rare families with dominant inheritance have been reported. We aimed to clinically, pathologically, and genetically characterize a large North American family with an autosomal dominant proximal SMA.Methods: Affected family members underwent clinical and electrophysiologic evaluation. Twenty family members were genotyped on high-density genome-wide SNP arrays and linkage analysis was performed.Results: Ten affected individuals (ages 7-58 years) showed prominent quadriceps atrophy, moderate to severe weakness of quadriceps and hip abductors, and milder degrees of weakness in other leg muscles. Upper extremity strength and sensation was normal. Leg weakness was evident from early childhood and was static or very slowly progressive. Electrophysiology and muscle biopsies were consistent with chronic denervation. SNP-based linkage analysis showed a maximum 2-point lod score of 5.10 ( ϭ 0.00) at rs17679127 on 14q32. A disease-associated haplotype spanning from 114 cM to the 14q telomere was identified. A single recombination narrowed the minimal genomic interval to Chr14: 100,220,368,585. No segregating copy number variations were found within the disease interval. Conclusions:We describe a family with an early onset, autosomal dominant, proximal SMA with a distinctive phenotype: symptoms are limited to the legs and there is notable selectivity for the quadriceps. We demonstrate linkage to a 6.1-Mb interval on 14q32 and propose calling this disorder spinal muscular atrophy-lower extremity, dominant. Neurology Spinal muscular atrophies (SMAs) are hereditary disorders characterized by degeneration of spinal cord motor neurons. The majority of SMA cases show autosomal recessive inheritance and are caused by homozygous deletion or mutation of the SMN1 gene on 5q (OMIM 253300, 253550, 253400, and 271150). Non-5q SMAs are rare, clinically diverse, and genetically heterogeneous.1,2 They are commonly classified by inheritance pattern and whether weakness involves predominantly distal or proximal musculature.The non-5q SMAs with distal-predominant weakness show phenotypic overlap with the distal hereditary motor neuropathies. Recessive disorders in this category are caused by mutations in IGHMBP2, 3 PLEKHG5, 4 or show linkage to 9p21.1-p12 5 or 11q.13. 6 Dominant

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Section: Clinical Featuresmentioning

confidence: 80%

“…Similar type II predominance has been reported in one other family. 28 The degree of fiber type predominance we have observed could originate from several potential mechanisms. First, successive rounds of denervation with reinnervation could produce what amounts to severe fiber type grouping.…”

Section: Clinical Featuresmentioning

confidence: 89%

Dominant spinal muscular atrophy with lower extremity predominance

et al. 2010

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“…This is in contrast to the distal weakness reported in dominant SMA families with TRPV4 mutations, suggesting this is a key clinical aspect in the differential diagnosis. 1,3,5,6 Joint contractures were not a predominant clinical feature of the original DYNC1H1 families, but were noted in almost half of our cohort (46.4%). In many cases, contractures were a presenting feature, were found almost exclusively in the lower limbs, and did not progress with time.…”

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confidence: 99%

Novel mutations expand the clinical spectrum of DYNC1H1 -associated spinal muscular atrophy

et al. 2015

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Objective: To expand the clinical phenotype of autosomal dominant congenital spinal muscular atrophy with lower extremity predominance (SMA-LED) due to mutations in the dynein, cytoplasmic 1, heavy chain 1 (DYNC1H1) gene. Methods:Patients with a phenotype suggestive of a motor, non-length-dependent neuronopathy predominantly affecting the lower limbs were identified at participating neuromuscular centers and referred for targeted sequencing of DYNC1H1.Results: We report a cohort of 30 cases of SMA-LED from 16 families, carrying mutations in the tail and motor domains of DYNC1H1, including 10 novel mutations. These patients are characterized by congenital or childhood-onset lower limb wasting and weakness frequently associated with cognitive impairment. The clinical severity is variable, ranging from generalized arthrogryposis and inability to ambulate to exclusive and mild lower limb weakness. In many individuals with cognitive impairment (9/30 had cognitive impairment) who underwent brain MRI, there was an underlying structural malformation resulting in polymicrogyric appearance. The lower limb muscle MRI shows a distinctive pattern suggestive of denervation characterized by sparing and relative hypertrophy of the adductor longus and semitendinosus muscles at the thigh level, and diffuse involvement with relative sparing of the anteriormedial muscles at the calf level. Proximal muscle histopathology did not always show classic neurogenic features. Conclusion:Our report expands the clinical spectrum of DYNC1H1-related SMA-LED to include generalized arthrogryposis. In addition, we report that the neurogenic peripheral pathology and the CNS neuronal migration defects are often associated, reinforcing the importance of DYNC1H1 in both central and peripheral neuronal functions. Neurology ® 2015;84:668-679 GLOSSARY ADHD 5 attention deficit hyperactivity disorder; BICD2 5 bicaudal D homolog 2 (Drosophila); CBCL 5 Child Behavior Checklist; DYNC1H1 5 dynein, cytoplasmic 1, heavy chain 1; LED 5 lower extremity predominance; Loa 5 legs at odd angles; MCD 5 malformation of cortical development; SMA 5 spinal muscular atrophy.

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“…[1][2][3][4][5][6][7][8] The most extensively studied condition in this group is autosomal recessive spinal muscular atrophy type I or Werdnig-Hoffmann's disease. 4 The primary defect in SMA lies in the lower motor neurons or anterior horn cells, which in some cases is shown by autopsy.…”

Section: Introductionmentioning

confidence: 99%

“…4 The primary defect in SMA lies in the lower motor neurons or anterior horn cells, which in some cases is shown by autopsy. A subset of SMA presents at birth with contractures and muscle atrophy, 1,5,7 suggesting a defect in the development of the anterior horn cells or early degeneration. 5 Therefore, the most likely time of onset is during or shortly after the third month of pregnancy, which is the critical period for differentiation of the spinal motor neurons.…”

Section: Introductionmentioning

confidence: 99%

Localisation of the gene for a dominant congenital spinal muscular atrophy predominantly affecting the lower limbs to chromosome 12q23–q24

et al. 1998

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Spinal muscular atrophies are a heterogeneous group of disorders. They differ in time of onset, clinical presentation, progression, severity and mode of inheritance. In 1985 a Dutch family was described with a dominant, nonprogressive spinal muscular atrophy presenting at birth with arthrogryposis (MIM 600175). Linkage analysis was performed in this family. After having excluded the loci for Werdnig-Hoffmann's disease and for dominant distal spinal muscular atrophy with upper limb predominance, we were able to localise the gene to a 10 cM interval between the markers D12S78 and D12S1646 on chromosome 12q23-q24. Recently, dominant scapuloperoneal spinal muscular atrophy has been localised to an overlapping interval. However, the clinical appearances of scapuloperoneal spinal muscular atrophy and the present disorder make allelism unlikely. In 1994, a second Dutch family with a disorder similar to the present one was described. We excluded linkage to markers of the 12q23-q24 region in this family and thereby proved genetic heterogeneity of this type of dominant, congenital and nonprogressive spinal muscular atrophy.

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A dominantly inherited lower motor neuron disorder presenting at birth with associated arthrogryposis.

Cited by 71 publications

References 11 publications

Dominant spinal muscular atrophy with lower extremity predominance

Dominant spinal muscular atrophy with lower extremity predominance

Novel mutations expand the clinical spectrum of DYNC1H1 -associated spinal muscular atrophy

Localisation of the gene for a dominant congenital spinal muscular atrophy predominantly affecting the lower limbs to chromosome 12q23–q24

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