Expanding the phenotype of DYNC1H1-associated diseases with a rare variant resulting in spinal muscular atrophy with lower extremity predominance (SMA-LED) and upper motor neuron signs
Background. Spinal muscular atrophy with lower extremity predominance (SMA-LED) is an autosomal dominant disorder. Since SMA-LED affects lower motor neurons, the disease is characterized by weakness and atrophy of lower limb muscles. We present a familial case series of SMA-LED with upper mot...
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Hacettepe University Institute of Child Health
2023-06-01
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| Series: | The Turkish Journal of Pediatrics |
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| Online Access: | https://turkjpediatr.org/article/view/59 |
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| author | Jessica Lee Philip Millington Kavinda Dayasiri Sithara Ramdas Sandeep Jayawant Geetha Anand |
| author_facet | Jessica Lee Philip Millington Kavinda Dayasiri Sithara Ramdas Sandeep Jayawant Geetha Anand |
| author_sort | Jessica Lee |
| collection | DOAJ |
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Background. Spinal muscular atrophy with lower extremity predominance (SMA-LED) is an autosomal dominant disorder. Since SMA-LED affects lower motor neurons, the disease is characterized by weakness and atrophy of lower limb muscles. We present a familial case series of SMA-LED with upper motor neuron signs associated with a rare variant in DYNC1H1.
Case. The index case was referred to Pediatric Neurology at the age of two and half years, due to delayed mobility. The child was diagnosed with congenital vertical talus at birth, which was managed with serial bilateral casting and surgery. The delayed mobility was initially attributed to lower limb weakness secondary to prolonged periods of immobilization from casting of his lower limbs. He had a striking waddling gait and proximal muscle weakness on neurological assessment. He had lower motor neuron signs predominantly in his lower limbs that were in keeping with SMA-LED. Surprisingly, he also demonstrated a brisk crossed adductor response that was not in keeping with an isolated primary neuro-muscular disorder and suggested a mixed upper and lower motor neuron pathology. The inherited neuropathy gene panel revealed a heterozygous sequence change in the DYNC1H1 gene which was present in all affected family members.
Conclusions. We present the first report of a familial case series of SMA-LED with upper motor neuron signs associated with an extremely rare variant in DYNC1H1: c.1808A > T (p.Glu603Val). As per the American College of Medical Genetics and Genomics (ACMG) guidelines for variant classification, we would recommend that this variant be reclassified as `Likely Pathogenic` due to matching 1 moderate (PM1-PM6) and ≥4 supporting (PP1-PP5) criteria in the reported case series.
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| format | Article |
| id | doaj-art-154bd0ab590f48ac8315bcf87f4addc7 |
| institution | OA Journals |
| issn | 0041-4301 2791-6421 |
| language | English |
| publishDate | 2023-06-01 |
| publisher | Hacettepe University Institute of Child Health |
| record_format | Article |
| series | The Turkish Journal of Pediatrics |
| spelling | doaj-art-154bd0ab590f48ac8315bcf87f4addc72025-08-20T02:00:50ZengHacettepe University Institute of Child HealthThe Turkish Journal of Pediatrics0041-43012791-64212023-06-0165310.24953/turkjped.2022.513Expanding the phenotype of DYNC1H1-associated diseases with a rare variant resulting in spinal muscular atrophy with lower extremity predominance (SMA-LED) and upper motor neuron signsJessica Lee0Philip Millington1Kavinda Dayasiri2Sithara Ramdas3Sandeep Jayawant4Geetha Anand5Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.Faculty of Medicine, University of Kelaniya, Sri Lanka, and, Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom.Oxford University Hospitals NHS Foundation Trust, Oxford, United Kingdom. Background. Spinal muscular atrophy with lower extremity predominance (SMA-LED) is an autosomal dominant disorder. Since SMA-LED affects lower motor neurons, the disease is characterized by weakness and atrophy of lower limb muscles. We present a familial case series of SMA-LED with upper motor neuron signs associated with a rare variant in DYNC1H1. Case. The index case was referred to Pediatric Neurology at the age of two and half years, due to delayed mobility. The child was diagnosed with congenital vertical talus at birth, which was managed with serial bilateral casting and surgery. The delayed mobility was initially attributed to lower limb weakness secondary to prolonged periods of immobilization from casting of his lower limbs. He had a striking waddling gait and proximal muscle weakness on neurological assessment. He had lower motor neuron signs predominantly in his lower limbs that were in keeping with SMA-LED. Surprisingly, he also demonstrated a brisk crossed adductor response that was not in keeping with an isolated primary neuro-muscular disorder and suggested a mixed upper and lower motor neuron pathology. The inherited neuropathy gene panel revealed a heterozygous sequence change in the DYNC1H1 gene which was present in all affected family members. Conclusions. We present the first report of a familial case series of SMA-LED with upper motor neuron signs associated with an extremely rare variant in DYNC1H1: c.1808A > T (p.Glu603Val). As per the American College of Medical Genetics and Genomics (ACMG) guidelines for variant classification, we would recommend that this variant be reclassified as `Likely Pathogenic` due to matching 1 moderate (PM1-PM6) and ≥4 supporting (PP1-PP5) criteria in the reported case series. https://turkjpediatr.org/article/view/59spinal muscular atrophy with lower extremity predominanceupper motor neuron signs |
| spellingShingle | Jessica Lee Philip Millington Kavinda Dayasiri Sithara Ramdas Sandeep Jayawant Geetha Anand Expanding the phenotype of DYNC1H1-associated diseases with a rare variant resulting in spinal muscular atrophy with lower extremity predominance (SMA-LED) and upper motor neuron signs The Turkish Journal of Pediatrics spinal muscular atrophy with lower extremity predominance upper motor neuron signs |
| title | Expanding the phenotype of DYNC1H1-associated diseases with a rare variant resulting in spinal muscular atrophy with lower extremity predominance (SMA-LED) and upper motor neuron signs |
| title_full | Expanding the phenotype of DYNC1H1-associated diseases with a rare variant resulting in spinal muscular atrophy with lower extremity predominance (SMA-LED) and upper motor neuron signs |
| title_fullStr | Expanding the phenotype of DYNC1H1-associated diseases with a rare variant resulting in spinal muscular atrophy with lower extremity predominance (SMA-LED) and upper motor neuron signs |
| title_full_unstemmed | Expanding the phenotype of DYNC1H1-associated diseases with a rare variant resulting in spinal muscular atrophy with lower extremity predominance (SMA-LED) and upper motor neuron signs |
| title_short | Expanding the phenotype of DYNC1H1-associated diseases with a rare variant resulting in spinal muscular atrophy with lower extremity predominance (SMA-LED) and upper motor neuron signs |
| title_sort | expanding the phenotype of dync1h1 associated diseases with a rare variant resulting in spinal muscular atrophy with lower extremity predominance sma led and upper motor neuron signs |
| topic | spinal muscular atrophy with lower extremity predominance upper motor neuron signs |
| url | https://turkjpediatr.org/article/view/59 |
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