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.

Quantitative neuromuscular ultrasound analysis as biomarkers in amyotrophic lateral sclerosis.

OBJECTIVES: To assess the differences in morphological and texture parameters of median nerve (MN) and abductor pollicis brevis (APB) between amyotrophic lateral sclerosis (ALS) patients and controls. METHODS: The cross-sectional area (CSA) of the MN and the muscle thickness (MTh) of APB were measured bilaterally in 59 recently diagnosed ALS patients and 20 matched healthy controls. Echointensity (EI), echovariation (EV) and grey-level co-occurrence matrix (GLCM) texture features of both structures were also analysed. Correlations between these parameters and clinical variables (muscle strength and disability) were analysed. RESULTS: The CSA of MN was significantly lower in ALS patients (MD = - 1.83 mm2 [95% CI = 2.89; - 0.77 mm2]; p = 0.01). ALS patients showed significantly lower MTh (- 2.23 mm [3.16; - 1.30 mm]; p < 0.001) and EV (- 7.40 [11.5; - 3.33]; p = 0.004) and higher EI (21.2 [11.9; 30.6]; p < 0.001) in the APB muscle. No relevant differences were detected in GLCM features for this muscle. The model including all parameters (CSA for MN and MTh, EI and EV for APB) showed an AUC of 82% (sensitivity 87%; specificity 42%). Muscle strength and disability correlated with APB muscle ultrasound parameters but not with those of the MN. CONCLUSIONS: APB muscle ultrasound biomarkers (especially MTh and EI) showed better discrimination capacity and correlation with clinical variables than MN biomarkers. However, the combination of both biomarkers increased their ability to detect LMN impairment, suggesting that both biomarkers could be used in a complementary manner for the diagnosis and progression monitoring in ALS. KEY POINTS: • Abductor pollicis brevis muscle and median nerve impairment is detectable by ultrasound in amyotrophic lateral sclerosis patients, even in those without clinical impairment. • Muscle ultrasound biomarkers show better discrimination capacity than nerve biomarkers in amyotrophic lateral sclerosis. • Quantitative neuromuscular ultrasound biomarkers could be useful in a general amyotrophic lateral sclerosis population early on the disease.

Netrin-1 receptor antibodies in thymoma-associated neuromyotonia with myasthenia gravis.

OBJECTIVE: To identify cell-surface antibodies in patients with neuromyotonia and to describe the main clinical implications. METHODS: Sera of 3 patients with thymoma-associated neuromyotonia and myasthenia gravis were used to immunoprecipitate and characterize neuronal cell-surface antigens using reported techniques. The clinical significance of antibodies against precipitated proteins was assessed with sera of 98 patients (neuromyotonia 46, myasthenia gravis 52, thymoma 42; 33 of them with overlapping syndromes) and 219 controls (other neurologic diseases, cancer, and healthy volunteers). RESULTS: Immunoprecipitation studies identified 3 targets, including the Netrin-1 receptors DCC (deleted in colorectal carcinoma) and UNC5A (uncoordinated-5A) as well as Caspr2 (contactin-associated protein-like 2). Cell-based assays with these antigens showed that among the indicated patients, 9 had antibodies against Netrin-1 receptors (7 with additional Caspr2 antibodies) and 5 had isolated Caspr2 antibodies. Only one of the 219 controls had isolated Caspr2 antibodies with relapsing myelitis episodes. Among patients with neuromyotonia and/or myasthenia gravis, the presence of Netrin-1 receptor or Caspr2 antibodies predicted thymoma (p < 0.05). Coexisting Caspr2 and Netrin-1 receptor antibodies were associated with concurrent thymoma, myasthenia gravis, and neuromyotonia, often with Morvan syndrome (p = 0.009). Expression of DCC, UNC5A, and Caspr2 proteins was demonstrated in paraffin-embedded thymoma samples (3) and normal thymus. CONCLUSIONS: Antibodies against Netrin-1 receptors (DCC and UNC5a) and Caspr2 often coexist and associate with thymoma in patients with neuromyotonia and myasthenia gravis. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that antibodies against Netrin-1 receptors can identify patients with thymoma (sensitivity 21.4%, specificity 100%).

Mutations in the MORC2 gene cause axonal Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease (CMT) is a complex disorder with wide genetic heterogeneity. Here we present a new axonal Charcot-Marie-Tooth disease form, associated with the gene microrchidia family CW-type zinc finger 2 (MORC2). Whole-exome sequencing in a family with autosomal dominant segregation identified the novel MORC2 p.R190W change in four patients. Further mutational screening in our axonal Charcot-Marie-Tooth disease clinical series detected two additional sporadic cases, one patient who also carried the same MORC2 p.R190W mutation and another patient that harboured a MORC2 p.S25L mutation. Genetic and in silico studies strongly supported the pathogenicity of these sequence variants. The phenotype was variable and included patients with congenital or infantile onset, as well as others whose symptoms started in the second decade. The patients with early onset developed a spinal muscular atrophy-like picture, whereas in the later onset cases, the initial symptoms were cramps, distal weakness and sensory impairment. Weakness and atrophy progressed in a random and asymmetric fashion and involved limb girdle muscles, leading to a severe incapacity in adulthood. Sensory loss was always prominent and proportional to disease severity. Electrophysiological studies were consistent with an asymmetric axonal motor and sensory neuropathy, while fasciculations and myokymia were recorded rather frequently by needle electromyography. Sural nerve biopsy revealed pronounced multifocal depletion of myelinated fibres with some regenerative clusters and occasional small onion bulbs. Morc2 is expressed in both axons and Schwann cells of mouse peripheral nerve. Different roles in biological processes have been described for MORC2. As the silencing of Charcot-Marie-Tooth disease genes have been associated with DNA damage response, it is tempting to speculate that a deregulation of this pathway may be linked to the axonal degeneration observed in MORC2 neuropathy, thus adding a new pathogenic mechanism to the long list of causes of Charcot-Marie-Tooth disease.