Facial onset sensory and motor neuronopathy: a motor neuron disease with an oligogenic origin?

Objective: To describe a patient with facial onset sensory and motor neuronopathy (FOSMN) carrying heterozygous mutations in both TARDBP and SQSTM1 genes. Methods: The patient underwent neurological, neuropsychological, and neurophysiological examinations. Brain magnetic resonance imaging (MRI) and extensive genetic analysis were also performed. Results: The neurological examination showed dysphonia, left trigeminal hypesthesia, and left masseter and temporalis muscle atrophy. Mild cognitive impairment, affecting predominantly executive functions and social cognition, was appreciable in the neuropsychological examination. The electrophysiological studies revealed: left abnormal blink reflex; neurogenic changes in bulbar and cervical muscles; normal motor evoked potential amplitude, central motor conduction time and cortical silent period. Brain MRI showed right-predominant frontotemporal atrophy. Genetic analysis showed a heterozygous mutation in TARDBP (p.A390S) and in SQSTM1 (p.P392L), both previously described as causing amyotrophic lateral sclerosis. The SQSTM1, but not the TARDBP, mutation was found in both healthy siblings. Conclusions: Our data provide new clinical, neuroimaging, and genetic evidence that FOSMN is a neurodegenerative disease of the motor neuron disease and frontotemporal dementia spectrum, with a possible oligogenic origin. Multicentric efforts focusing on cognitive and genetic studies are necessary to confirm this hypothesis and to determine if ALS genes should be systematically screened in these patients.

New mutations found by Next-Generation Sequencing screening of Spanish patients with Nemaline Myopathy.

Nemaline Myopathy (NM) is a rare genetic disorder that encompasses a large spectrum of myopathies characterized by hypotonia and generalized muscle weakness. To date, mutations in thirteen different genes have been associated with NM. The most frequently responsible genes are NEB (50% of cases) and ACTA1 (15-25% of cases). In this report all known NM related genes were screened by Next Generation Sequencing in five Spanish patients in order to genetically confirm the clinical and histological diagnosis of NM. Four mutations in NEB (c.17779_17780delTA, c.11086A>C, c.21076C>T and c.2310+5G>A) and one mutation in ACTA1 (c.871A>T) were found in four patients. Three of the four mutations in NEB were novel. A cDNA sequencing assay of the novel variants c.17779_17780delTA, c.11086A>C and c.2310+5G>A revealed that the intronic variant c.2310+5G>A affected the splicing process. Mutations reported here could help clinicians and geneticists in NM diagnosis.