Emily C. Oates

Genome-wide profiling of p63 DNA-binding sites identifies an element that regulates gene expression during limb development in the 7q21 SHFM1 locus.

Heterozygous mutations in p63 are associated with split hand/foot malformations (SHFM), orofacial clefting, and ectodermal abnormalities. Elucidation of the p63 gene network that includes target genes and regulatory elements may reveal new genes for other malformation disorders. We performed genome-wide DNA–binding profiling by chromatin immunoprecipitation (ChIP), followed by deep sequencing (ChIP–seq) in primary human keratinocytes, and identified potential target genes and regulatory elements controlled by p63. We show that p63 binds to an enhancer element in the SHFM1 locus on chromosome 7q and that this element controls expression of DLX6 and possibly DLX5, both of which are important for limb development. A unique micro-deletion including this enhancer element, but not the DLX5/DLX6 genes, was identified in a patient with SHFM. Our study strongly indicates disruption of a non-coding cis-regulatory element located more than 250 kb from the DLX5/DLX6 genes as a novel disease mechanism in SHFM1. These data provide a proof-of-concept that the catalogue of p63 binding sites identified in this study may be of relevance to the studies of SHFM and other congenital malformations that resemble the p63-associated phenotypes.

Mutations in BICD2 Cause Dominant Congenital Spinal Muscular Atrophy and Hereditary Spastic Paraplegia

Dominant congenital spinal muscular atrophy (DCSMA) is a disorder of developing anterior horn cells and shows lower-limb predominance and clinical overlap with hereditary spastic paraplegia (HSP), a lower-limb-predominant disorder of corticospinal motor neurons. We have identified four mutations in bicaudal D homolog 2 (Drosophila) (BICD2) in six kindreds affected by DCSMA, DCSMA with upper motor neuron features, or HSP. BICD2 encodes BICD2, a key adaptor protein that interacts with the dynein-dynactin motor complex, which facilitates trafficking of cellular cargos that are critical to motor neuron development and maintenance. We demonstrate that mutations resulting in amino acid substitutions in two binding regions of BICD2 increase its binding affinity for the cytoplasmic dynein-dynactin complex, which might result in the perturbation of BICD2-dynein-dynactin-mediated trafficking, and impair neurite outgrowth. These findings provide insight into the mechanism underlying both the static and the slowly progressive clinical features and the motor neuron pathology that characterize BICD2-associated diseases, and underscore the importance of the dynein-dynactin transport pathway in the development and survival of both lower and upper motor neurons.

Neuromuscular junction abnormalities in DNM2-related centronuclear myopathy

Dynamin-2-related centronuclear myopathy (DNM2-CNM) is a clinically heterogeneous muscle disorder characterized by muscle weakness and centralized nuclei on biopsy. There is little known about the muscle dysfunction underlying this disorder, and there are currently no treatments. In this study, we establish a novel zebrafish model for DNM2-CNM by transiently overexpressing a mutant version of DNM2 (DNM2-S619L) during development. We show that overexpression of DNM2-S619L leads to pathological changes in muscle and a severe motor phenotype. We further demonstrate that the muscle weakness seen in these animals can be significantly alleviated by treatment with an acetylcholinesterase inhibitor. Based on these results, we reviewed the clinical history of five patients with two different DNM2-CNM mutations (S619L and E368K) and found electrophysiological evidence of abnormal neuromuscular transmission in two of the individuals. All five patients showed improved muscle strength and motor function, and/or reduced fatigability following acetylcholinesterase inhibitor treatment. Together, our results suggest that deficits at the neuromuscular junction may play an important role in the pathogenesis of DNM2-CNM and that treatments targeting this dysfunction can provide an effective therapy for patients with this disorder.

Loss-of-function mutations in SCN4A cause severe foetal hypokinesia or 'classical' congenital myopathy

See Cannon (doi: 10.1093/brain/awv400 ) for a scientific commentary on this article. Dominant gain-of-function mutations in SCN4A , which encodes the α-subunit of the voltage-gated sodium channel, are a common cause of myotonia and periodic paralysis. Zaharieva et al. now report recessive loss-of-function SCN4A mutations in 11 patents with congenital myopathy. The mutations cause fully non-functional channels or result in reduced channel activity.

Longitudinal assessment of cognition and T2-hyperintensities in NF1: an 18-year study.

The developmental course of cognitive deficits in individuals with neurofibromatosis type 1 (NF1) is unclear. The objectives of this study were to determine the natural history of cognitive function and MRI T2‐hyperintesities (T2H) from childhood to adulthood and to examine whether the presence of discrete T2H in childhood can predict cognitive performance in adulthood. We present cognitive and structural neuroimaging data from 18 patients with NF1 and five sibling controls assessed prospectively across an 18‐year period. Longitudinal analyses revealed a significant increase in general cognitive function in patients with NF1 over the study period. Improvements were limited to individuals with discrete T2H in childhood. Patients without lesions in childhood exhibited a stable profile. The number of T2H decreased over time, particularly discrete lesions. Lesions located within the cerebral hemispheres and deep white matter were primarily stable, whereas those located in the basal ganglia, thalamus and brainstem tended to resolve. Our results support the hypothesis that resolution of T2H is accompanied by an improvement in general cognitive performance, possibly as a result of increased efficiency within white matter tracts.

Autosomal dominant congenital spinal muscular atrophy: a true form of spinal muscular atrophy caused by early loss of anterior horn cells

Autosomal dominant congenital spinal muscular atrophy is characterized by predominantly lower limb weakness and wasting, and congenital or early-onset contractures of the hip, knee and ankle. Mutations in TRPV4, encoding a cation channel, have recently been identified in one large dominant congenital spinal muscular atrophy kindred, but the genetic basis of dominant congenital spinal muscular atrophy in many families remains unknown. It has been hypothesized that differences in the timing and site of anterior horn cell loss in the central nervous system account for the variations in clinical phenotype between different forms of spinal muscular atrophy, but there has been a lack of neuropathological data to support this concept in dominant congenital spinal muscular atrophy. We report clinical, electrophysiology, muscle magnetic resonance imaging and histopathology findings in a four generation family with typical dominant congenital spinal muscular atrophy features, without mutations in TRPV4, and in whom linkage to other known dominant neuropathy and spinal muscular atrophy genes has been excluded. The autopsy findings in the proband, who died at 14 months of age from an unrelated illness, provided a rare opportunity to study the neuropathological basis of dominant congenital spinal muscular atrophy. There was a reduction in anterior horn cell number in the lumbar and, to a lesser degree, the cervical spinal cord, and atrophy of the ventral nerve roots at these levels, in the absence of additional peripheral nerve pathology or abnormalities elsewhere along the neuraxis. Despite the young age of the child at the time of autopsy, there was no pathological evidence of ongoing loss or degeneration of anterior horn cells suggesting that anterior horn cell loss in dominant congenital spinal muscular atrophy occurs in early life, and is largely complete by the end of infancy. These findings confirm that dominant congenital spinal muscular atrophy is a true form of spinal muscular atrophy caused by a loss of anterior horn cells localized to lumbar and cervical regions early in development.

Young Australian adults with NF1 have poor access to health care, high complication rates, and limited disease knowledge†

Neurofibromatosis type 1 (NF1) is a multisystem disease associated with a lifelong risk of debilitating and potentially life‐limiting complications, however many adults with NF1 have no regular health surveillance. We interviewed and examined 17 young adults with NF1 between the ages of 25 and 33. Most had not been assessed for NF1‐related complications within the previous 8 years, including patients with known serious vascular complications, for example, renal artery stenosis. Acute and/or chronic pain, particularly back and plexiform‐related pain were common symptoms, and despite a significant impact on quality of life, was untreated in most instances. Symptom and examination‐directed imaging revealed serious complications in 41% of the cohort. These included severe spinal cord compression (two cases), a highly SUV avid lesion suggestive of malignancy (one case), and a Juvenile Pilocytic Astrocytoma in a patient without any previous NF1‐related complications. Few study participants had a good understanding of NF1, its associated risks and complications, and many had not sought appropriate medical advice as questions or problems arose. NF1‐related cognitive deficits in some participants, and the lack of a clear source of expert medical advice for adults with NF1 likely contributed to poor health surveillance and management in this population. Overall, these findings suggest that many Australian adults with NF1 are at risk of serious and life‐threatening medical complications, but are not accessing and receiving adequate health care. Access to multidisciplinary adult clinics that specialize in NF1 may address many of the unmet health needs of young adults with NF1.

Diagnosis and etiology of congenital muscular dystrophy: We are halfway there

To evaluate the diagnostic outcomes in a large cohort of congenital muscular dystrophy (CMD) patients using traditional and next generation sequencing (NGS) technologies.

Recessive ACTA1 variant causes congenital muscular dystrophy with rigid spine

Variants in ACTA1, which encodes α-skeletal actin, cause several congenital myopathies, most commonly nemaline myopathy. Autosomal recessive variants comprise approximately 10% of ACTA1 myopathy. All recessive variants reported to date have resulted in loss of skeletal α-actin expression from muscle and severe weakness from birth. Targeted next-generation sequencing in two brothers with congenital muscular dystrophy with rigid spine revealed homozygous missense variants in ACTA1. Skeletal α-actin expression was preserved in these patients. This report expands the clinical and histological phenotype of ACTA1 disease to include congenital muscular dystrophy with rigid spine and dystrophic features on muscle biopsy. This represents a new class of recessive ACTA1 variants, which do not abolish protein expression.

The p.Ser107Leu in BICD2 is a mutation ‘hot spot’ causing distal spinal muscular atrophy

1 The John Walton Muscular Dystrophy Research Centre, MRC Centre for Neuromuscular Diseases, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK 2 Wellcome Trust Centre for Mitochondrial Research, Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK 3 Department of Paediatric Neurology, Royal Victoria Infirmary, Newcastle upon Tyne Foundation Hospitals NHS Trust, Newcastle upon Tyne, UK