Electrophysiological and motor function scale association in a pre-symptomatic infant with spinal muscular atrophy type I
ABSTRACT A term infant, at familial risk for spinal muscular atrophy (SMA), had the diagnosis genetically confirmed on day 3 of life. Clinical evaluation, the CHOP INTEND motor scale and the CMAP amplitude were obtained on days 5 (pre-symptomatic), 20 (mildly weak), 34 (moderately weak) and 63 (severely weak). Palliative care was provided and he expired of an acute pulmonary infection on day 81. The CMAP amplitude and INTEND scores were initially in the normal range, then followed a corresponding decline to a nadir at day 34 and remained so at the 4th assessment. A log-transformed plot of CMAP amplitude from days 5-34 was linear. These data suggest that early motor neuron loss in SMA type I may be logarithmic and demonstrates that the INTEND motor scale closely follows the CMAP electrophysiological biomarker. This single case report supports the consideration that early intervention with a potential therapy is necessary, before the pool of functional motor neurons has plummeted. Further study of these parameters in pre-symptomatic infants with SMA type I will help guide the design of future intervention studies.
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ABSTRACT: Spinal muscular atrophy (SMA) describes a group of disorders associated with spinal motor neuron loss. In this review we provide an update regarding the most common form of SMA, proximal or 5q SMA, and discuss the contemporary approach to diagnosis and treatment. Electromyography and muscle biopsy features of denervation were once the basis for diagnosis, but molecular testing for homozygous deletion or mutation of the SMN1 gene allows efficient and specific diagnosis. In combination with loss of SMN1, patients retain variable numbers of copies of a second similar gene, SMN2, which produce reduced levels of the survival motor neuron (SMN) protein that are insufficient for normal motor neuron function. Despite the fact that the understanding of how ubiquitous reduction of SMN protein leads to motor neuron loss remains incomplete, several promising therapeutics are now being tested in early phase clinical trials. © 2014 Wiley Periodicals, Inc.Muscle & Nerve 02/2015; 51(2). DOI:10.1002/mus.24497 · 2.31 Impact Factor
Muscle & Nerve 09/2014; 50(3). DOI:10.1002/mus.24318 · 2.31 Impact Factor
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ABSTRACT: Objectives Spinal muscular atrophy (SMA) is caused by reduced levels of survival motor neuron (SMN) protein, which results in motoneuron loss. Therapeutic strategies to increase SMN levels including drug compounds, antisense oligonucleotides, and scAAV9 gene therapy have proved effective in mice. We wished to determine whether reduction of SMN in postnatal motoneurons resulted in SMA in a large animal model, whether SMA could be corrected after development of muscle weakness, and the response of clinically relevant biomarkers.Methods Using intrathecal delivery of scAAV9 expressing an shRNA targeting pig SMN1, SMN was knocked down in motoneurons postnatally to SMA levels. This resulted in an SMA phenotype representing the first large animal model of SMA. Restoration of SMN was performed at different time points with scAAV9 expressing human SMN (scAAV9-SMN), and electrophysiology measurements and pathology were performed.ResultsKnockdown of SMN in postnatal motoneurons results in overt proximal weakness, fibrillations on electromyography indicating active denervation, and reduced compound muscle action potential (CMAP) and motor unit number estimation (MUNE), as in human SMA. Neuropathology showed loss of motoneurons and motor axons. Presymptomatic delivery of scAAV9-SMN prevented SMA symptoms, indicating that all changes are SMN dependent. Delivery of scAAV9-SMN after symptom onset had a marked impact on phenotype, electrophysiological measures, and pathology.InterpretationHigh SMN levels are critical in postnatal motoneurons, and reduction of SMN results in an SMA phenotype that is SMN dependent. Importantly, clinically relevant biomarkers including CMAP and MUNE are responsive to SMN restoration, and abrogation of phenotype can be achieved even after symptom onset. Ann Neurol 2015Annals of Neurology 12/2014; DOI:10.1002/ana.24332 · 11.91 Impact Factor