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.

Running title: BICD2 ablation in muscle causes motor neuron loss Characters (excluding spaces): 18,564 Summary Missense mutations in the cargo adaptor protein BICD2 cause SMALED2, a developmental disease of motor neurons. In this study, the authors show that BICD2 mutations cause motor neuron loss by a non-cell autonomous mechanism determining a disabling impairment of muscle function.3 Abstract BICD2 is a key component of the dynein/dynactin motor complex. Autosomal dominant mutations in BICD2 cause Spinal Muscular Atrophy Lower Extremity Predominant 2 (SMALED2), a developmental disease of motor neurons. In this study we sought to examine the motor neuron phenotype of conditional Bicd2 -/mice. Bicd2 -/mice show a significant reduction in the number of motor axons of the L4 ventral root compared to wild type mice. Muscle-specific knockout of Bicd2, but not motor neuronspecific Bicd2 loss, results in a reduction in L4 ventral axons comparable to global Bicd2 -/mice. Rab6, a small GTPase required for the sorting of secretory vesicles from the TGN to the plasma membrane is a major binding partner of BICD2. We therefore examined the secretory pathway in SMALED2 patient fibroblasts and demonstrated impaired flow of constitutive secretory cargoes. Together, these data indicate that BICD2 loss from muscles is a major driver of non-cell autonomous pathology with important implications for future therapeutic approaches to SMALED2.

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During the last decade, mutations in three small heat shock proteins (Hsps) HSPB1, HSPB3 and HSPB8 have been identified as causative of distal hereditary motor neuropathy (dHMN). Hsps are a ubiquitously expressed family of molecular chaperones with versatile functions that include refolding of misfolded proteins. Hsp70, the archetypal ATP-dependent Hsp, binds misfolded proteins with weak affinity. J domain (HSP40) proteins bind to HSP70, thereby increasing its protein binding and refolding capacity. In 2008, an autosomal recessive form of dHMN was described due to homozygous mutations in the Hsp40 gene, HSJ1. We have preliminary evidence that HSJ1 knockout mice develop de novo motor neuron (MN) degeneration, providing a model for this new form of dHMN. In this study, MNs from HSJ1 +/+ and HSJ1 −/− mice have been examined in vitro in primary MN cultures. We examined the effects of HSJ1 ablation on the stress response in MNs. We found that HSJ−/− MNs display an enhanced ER stress response compared to +/+ MNs in response to heat shock. Thus, HSJ−/− cells upregulate the expression of ER stress markers, such as the ER resident heat shock protein BiP. We also examined functional markers of MN function including axonal transport but found that the transport of mitochondria in HSJ −/− cells was unaffected. Thus, HSJ −/− primary motoneurons display some of the pathological hallmarks of dHMN and therefore can be a suitable model to study the mechanism of disease.