Type III Spinal Muscular Atrophy Mimicking Muscular Dystrophies

Types III and IV spinal muscular atrophy represent a diagnostic challenge due to the great variability in their presentation. We report a series of eight patients with type III spinal muscular atrophy who were followed for a long time for possible muscular dystrophy or myopathy, confirming its clinical heterogeneity and propensity to delayed diagnosis. Clinical examination revealed heterogeneous findings, where the diagnosis of type III spinal muscular atrophy was not immediately apparent in many patients as their clinical and laboratory abnormalities were consistent with muscular dystrophy or myopathy. The presence of dystrophic features such as hypertrophy of the calves, weakness of the limb girdle, high serum creatine kinase levels, and myopathic histopathology should not divert attention from the possibility of spinal muscular atrophy. It is strongly recommended to give variable presentations enough thought and to consider the autosomal recessive type III spinal muscular atrophy in the diagnostic evaluation.     

Treatment Advances in Spinal Muscular Atrophy

Purpose of Review

Spinal muscular atrophy (SMA) is a genetic disorder of motor neurons in the anterior horns of the spinal cord and brainstem that results in muscle atrophy and weakness. SMA is an autosomal recessive disease linked to deletions of the SMN1 gene on chromosome 5q. Humans have a duplicate gene (SMN2) whose product can mitigate disease severity, leading to the variability in severity and age of onset of disease, and is therefore a target for drug development.

Recent Findings

Advances in preclinical and clinical trials have paved the way for novel therapeutic options for SMA patients, including many currently in clinical trials. In 2016, the first treatment for SMA has been approved in the USA, an antisense oligonucleotide that increases full-length protein product derived from SMN2.

Summary

The approval of a first treatment for SMA and the rapid advances in clinical trials provide the prospect for multiple approaches to disease modification. There are several other promising therapeutics in different stages of development, based on approaches such as neuroprotection, or gene therapy.

     

The Genetics of Spinal Muscular Atrophy: Progress and Challenges

Spinal muscular atrophies (SMAs) are a group of inherited disorders characterized by motor neuron loss in the spinal cord and lower brainstem, muscle weakness, and atrophy. The clinical and genetic phenotypes incorporate a wide spectrum that is differentiated based on age of onset, pattern of muscle involvement, and inheritance pattern. Over the past several years, rapid advances in genetic technology have accelerated the identification of causative genes and provided important advances in understanding the molecular and biological basis of SMA and insights into the selective vulnerability of the motor neuron. Common pathophysiological themes include defects in RNA metabolism and splicing, axonal transport, and motor neuron development and connectivity. Together these have revealed potential novel treatment strategies, and extensive efforts are being undertaken towards expedited therapeutics. While a number of promising therapies for SMA are emerging, defining therapeutic windows and developing sensitive and relevant biomarkers are critical to facilitate potential success in clinical trials. This review incorporates an overview of the clinical manifestations and genetics of SMA, and describes recent advances in the understanding of mechanisms of disease pathogenesis and development of novel treatment strategies.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-014-0314-x) contains supplementary material, which is available to authorized users.     

脊髓性肌萎缩症的快速基因诊断研究

目的研究我国近端型脊髓性肌萎缩症（ＳＭＡ）患者的运动神经元生存基因（ＳＭＮ）外显子的缺失情况,探讨其快速基因诊断的可行性和临床应用价值。方法应用ＰＣＲ－酶切法检测２６例确诊的ＳＭＡ患者及２０名正常对照ＳＭＮ基因的第７、８号外显子的缺失情况。结果在２６例及２５例患者中,分别发现缺失了端粒ＳＭＮ基因（ＳＭＮ１）的第７和８号外显子,缺失率达１００％（２６／２６）和９６％（２５／２６）,而正常对照及患者的家系成员均未发现外显子缺失。结论应用ＰＣＲ－酶切法检测ＳＭＮ１基因缺失从而进行ＳＭＡ患者的基因诊断,具有准确、简便和快速的优点。     

New Therapeutic Approaches to Spinal Muscular Atrophy

Bench to bedside progress has been widely anticipated for a growing number of neurodegenerative disorders. Of these, spinal muscular atrophy (SMA) is perhaps the best poised to capitalize on advances in targeted therapeutics development over the next few years. Several laboratories have achieved compelling success in SMA animal models using sophisticated methods for targeted delivery, repair, or increased expression of the survival motor neuron protein, SMN. The clinical community is actively collaborating to identify, develop, and validate outcome measures and biomarkers in parallel with laboratory efforts. Innovative trial design and synergistic approaches to maximize proactive care in conjunction with treatment with one or more of the promising pharmacologic and biologic therapies currently in the pipeline will maximize our chances to achieve meaningful outcomes for patients. This review highlights recent promising scientific and clinical advances bringing us ever closer to effective treatment(s) for our patients with SMA.     

Monomelic Juvenile Spinal Muscular Atrophy of the Arm

In 3 patients with monomelic juvenile spinal muscular atrophy, T2-weighted and gradient-echo sagittal magnetic resonance images (MRIs) demonstrated cord atrophy at the C6-7 level. T1-weighted and gradient-echo axial images revealed cord flattening at the C6-7 level. Gradient-echo axial images showed high intensity from the anterior horns to the lateral columns bilaterally at C5-7 in 1 patient and in the right anterior horns at C5-7 in 2. With the neck flexed, T1-weighted and gradient-echo sagittal images of all patients showed narrowing and anterior shifting of the dural sac, corresponding to the localized atrophy, and also congestion of the internal vertebral venous plexus. These findings correlated to clinical features and with necropsy results. The distribution of spinal cord lesions approximates the watershed areas between the central and the peripheral arteries.     

An Unusual Inheritance Pattern for Spinal Muscular Atrophy

Progressive spinal muscular atrophy in infancy (Werdnig-Hoffmann's Disease) is considered to be inherited as an autosomal recessive trait. This paper reports the occurrence of this process in first cousins which, in addition to other examples in the literature, suggests an alternate pattern of genetic transmission. Possible modes of inheritance are discussed, particularly that of a dominant inheritance requiring an allelomorphic activator gene for phenotypic expression.

RÉSUMÉ

On considère que 'amyotrophie spinale infantile (Werdnig-Hoffmann) est transmise selon le mode autosomique récessif. Cette étude rapporte la survenue de cas chez des cousins germains, ce qui suggère, en association avec autres cas de la littérature, un autre type de transmission héréditaire. Les modes possibles de transmission sont discutés, en particulier celui un caractère dominant nécessitant un géne activateur allélomorphe pour parvenir à 'expression phénotypique.

ZUSAMMENFASSUNG

Die progressive spinale Muskelatrophie (Werdnig-Hoffman' sche Krankheit) bei Kindern wird als eine autosomal rezessive Erbkrankheit betrachtet. Diese Arbeit berichtet iiber einen derartigen Fall bei Vettern ersten Grades, woraus zusammen mit anderen Beispielen aus der Literatur ein anderer Weg der genetischen übertragung erörtert wird. Die Möglichkeiten des Erbganges werden diskutiert, vor allem eine dominante Vererbung, wobei für die phänotypische Erscheinung ein allelomorphisches Aktivatorgen benötigt wird.