A Recurrent De Novo Nonsense Variant in ZSWIM6 Results in Severe Intellectual Disability without Frontonasal or Limb Malformations.

A recurrent de novo missense variant within the C-terminal Sin3-like domain of ZSWIM6 was previously reported to cause acromelic frontonasal dysostosis (AFND), an autosomal-dominant severe frontonasal and limb malformation syndrome, associated with neurocognitive and motor delay, via a proposed gain-of-function effect. We present detailed phenotypic information on seven unrelated individuals with a recurrent de novo nonsense variant (c.2737C>T [p.Arg913Ter]) in the penultimate exon of ZSWIM6 who have severe-profound intellectual disability and additional central and peripheral nervous system symptoms but an absence of frontonasal or limb malformations. We show that the c.2737C>T variant does not trigger nonsense-mediated decay of the ZSWIM6 mRNA in affected individual-derived cells. This finding supports the existence of a truncated ZSWIM6 protein lacking the Sin3-like domain, which could have a dominant-negative effect. This study builds support for a key role for ZSWIM6 in neuronal development and function, in addition to its putative roles in limb and craniofacial development, and provides a striking example of different variants in the same gene leading to distinct phenotypes.

Differentiating lower motor neuron syndromes.

Lower motor neuron (LMN) syndromes typically present with muscle wasting and weakness and may arise from pathology affecting the distal motor nerve up to the level of the anterior horn cell. A variety of hereditary causes are recognised, including spinal muscular atrophy, distal hereditary motor neuropathy and LMN variants of familial motor neuron disease. Recent genetic advances have resulted in the identification of a variety of disease-causing mutations. Immune-mediated disorders, including multifocal motor neuropathy and variants of chronic inflammatory demyelinating polyneuropathy, account for a proportion of LMN presentations and are important to recognise, as effective treatments are available. The present review will outline the spectrum of LMN syndromes that may develop in adulthood and provide a framework for the clinician assessing a patient presenting with predominantly LMN features.

Clinical features of patients with Guillain-Barré syndrome at seven hospitals on the East Coast of Australia.

To document the clinical features of Guillain-Barré syndrome (GBS) in Australia, we performed a retrospective analysis of all patients admitted to several hospitals along the East Coast of Australia from 2000 to 2012. Using hospital records, we reviewed all patients with a diagnosis of GBS admitted to seven hospitals. From these, we report information of subjects who fulfilled standard diagnostic criteria. We excluded patients where inadequate information was available or who were under the age of 18. We report the features of 335 patients, in 228 of whom neurophysiological data were available. There were 168 cases of acute inflammatory demyelinating polyneuropathy (AIDP), 17 of acute motor axonal neuropathy (AMAN), 4 of acute motor and sensory axonal neuropathy (AMSAN), and 35 of Miller-Fisher syndrome (MFS). The median age at onset was 52.5 years (18-89 years) with a male : female ratio of 1.61 : 1. Upper respiratory tract infections were the most frequently identified trigger (151 subjects, 44.5%). Most patients were severely affected, with 42.7% of subjects bedbound, and an additional 24% requiring ventilatory support. GBS affects adults of all ages and usually follows a severe clinical course. In contrast to other autoimmune diseases, males are more frequently affected. A wide variety of triggering factors leads to a relatively stereotypical clinical syndrome. The most common variant of GBS in Australia is AIDP. This study shows that the clinical features of GBS in Australia are similar to that previously reported and confirms the male predominance, increased incidence with age, and frequent evidence of peripheral nerve demyelination as features of GBS.

Killer immunoglobulin-like receptor and their HLA ligands in Guillain-Barré Syndrome.

Guillain-Barré Syndrome (GBS) is an inflammatory neuropathy that occurs in some individuals after exposure to an infectious illness. We investigated the role of Killer-immunoglobulin-like receptors (KIR) and their HLA ligands as potential genetic factors in the pathogenesis of GBS. These receptors are involved in the innate immune response to infections. Whilst no significant differences in the frequencies KIR genes were found, HLA-C2 and HLA-B Bw4-T were more frequent in subjects with GBS than controls (p<0.001). The inhibitory pairs KIR-2DL2/HLA-C2 and KIR-3DL1/HLA-B Bw4-T were more frequent in GBS than controls (all p<0.005). We propose that NK cell inhibition is an important factor in the pathogenesis of GBS.