A step toward essential tremor gene discovery: identification of extreme phenotype and screening of HTRA2 and ANO3.

BACKGROUND: Essential tremor (ET) is characterized by a frequent family history. No monogenic form of ET has been identified. We aimed at exploring ET patients to identify distinct subgroups and facilitate the identification of ET genes. We tested for the presence of HTRA2 p.G399S, and ANO3 p. W490C, p. R484 W and p. S685G mutations. METHODS: Between June 2011 and November 2013, all consecutive patients suspected with ET were prospectively included in a prospective, monocentric study. Family history, age at onset (AAO), features of tremor, benefit of alcohol and drugs, electrophysiological recording findings were collected. Sanger sequencing was performed for HTRA2 and ANO3 mutations screening. RESULTS: Sixty eight patients were investigated. Fourteen diagnosed with psychogenic (5) or dystonic tremor (9) were excluded. Regarding the 54 ET patients, mean AAO was 48 years (6-77), and mean disease duration 15 years (1-55). Bimodal distribution of AAO was consistent with phenotypic subgroups. In patients with AAO before 30 years, marked benefit of alcohol (p < 0.01) and ET family history (p < 0.01) were more frequent and the disease progression less severe (p < 0.0001). Neither HTRA2 nor ANO3 mutation were identified in our patients. CONCLUSIONS: Our data support that distinct ET phenotypic subgroups may be encountered. We recommend to study separately extreme phenotypes of ET, particularly autosomal dominant families with early AAO (<30 years) and marked benefit of alcohol, to facilitate the identification of ET genes. Electromyographic recording remains a support to distinguish ET from differential diagnosis. HTRA2 and ANO3 mutations are not common causes of ET.

Relevance of corpus callosum splenium versus middle cerebellar peduncle hyperintensity for FXTAS diagnosis in clinical practice.

Fragile X-associated tremor ataxia syndrome (FXTAS) is caused by FMR1 premutation. The features include ataxia, action tremor and middle cerebellar peduncle (MCP) hyperintensity, the latter being the only major radiological criterion in the diagnosis of definite FXTAS until very recently. The importance of corpus callosum splenium (CCS) hyperintensity was recently reported and this sign is now considered as an additional major radiological diagnostic criterion in the diagnosis of FXTAS. However, little is known about its relevance for the diagnosis of FXTAS in clinical practice. We report a practical justification of the relevance of CCS hyperintensity in parallel with MCP hyperintensity for the diagnosis of FXTAS. Clinical and radiological study of 22 FMR1 premutation carriers with neurological signs that may be encountered in FXTAS compared to series of patients with essential tremor, multiple system atrophy of cerebellar type, Parkinson's disease, Alzheimer's disease and stroke. Among the 22 patients with FMR1 premutation [17 men, 5 women; mean age, 63 ± 7.5 (46-84)], 14 were diagnosed with definite FXTAS with the initial criteria. Considering CCS hyperintensity as a new major radiological criterion permitted the diagnosis of definite FXTAS in 3 additional patients. Overall CCS proved as frequent as MCP hyperintensity (64 versus 64 %), while 23 % of patients had CCS but not MCP hyperintensity, 14 % of patients had CCS hyperintensity but neither MCP, nor brainstem hyperintensity. In contrast with CCS hyperintensity, MCP hyperintensity proved less frequent in women than in men. CCS and MCP hyperintensity were more frequent in FXTAS than in the other neurodegenerative disorders. The combination of CCS and MCP hyperintensity was specific of FXTAS. We confirmed the relevance of CCS hyperintensity in FXTAS and we clarified its interest compared to MCP hyperintensity. Our results support the inclusion of CCS hyperintensity in the diagnostic criteria as a new major radiological criterion.

Lyme optic neuritis.

Lyme optic neuritis (ON) is a rare disease and only a few cases have been reported. We describe two cases of isolated Lyme ON, one with recurrence 9 months after the appearance of initial symptoms. Diagnosis criteria for multiple sclerosis and neuromyelitis optica were not met. The etiological diagnosis was based on European case definition criteria for neuroborreliosis. Both patients had positive serum and cerebrospinal fluid serology, a positive intrathecal anti-Borrelia antibody index, and a good outcome on ceftriaxone. Specific diagnosis of Lyme ON is important since improvement of visual acuity is possible with specific antibiotherapy, even after many months.

Diffusion-weighted imaging in noncompressive myelopathies: a 33-patient prospective study.

Diffusion-weighted imaging (DWI) is frequently used to differentiate cerebral lesions. The aim of our study was to evaluate the diagnostic value of DWI and the measurement of the apparent diffusion coefficient (ADC) in noncompressive myelopathy explorations. Thirty-three patients presenting a spinal cord syndrome due to a noncompressive myelopathy underwent spinal cord MRI between September 2005 and November 2008. For each patient, the ADC was calculated in the pathological spinal cord. ADC values were also measured in the healthy spinal cord of ten control subjects. Statistical analysis was based on the Student's t test. Twenty-one patients presented an inflammatory myelopathy: Nine patients presented multiple sclerosis, three patients presented a parainfectious myelopathy, two patients acute disseminated encephalomyelitis, one patient neuromyelitis optica, one patient systemic lupus erythematosus, and five patients a myelopathy of unknown aetiology. Six patients presented a spinal cord infarction. ADC values were significantly lower in spinal cord infarct (mean ADC = 0.81 +/- 0.08 x 10(-3) mm(2)/s) than in inflammatory spinal cord lesions (mean ADC = 1.37 +/- 0.23 x 10(-3) mm(2)/s) and in healthy control spinal cord (mean ADC = 0.93 +/- 0.07 x 10(-3) mm(2)/s). These results are important to differentiate ischaemic from inflammatory myelopathies, especially at the acute phase when clinical presentation and extensive work-up are not able to show an aetiologic diagnosis. Although these results are similar to those described in cerebral explorations, ADC measurements remain technically limited for the moment.

Magnetic resonance spectroscopy evaluation in patients with neuromyelitis optica.

OBJECTIVE: Neuromyelitis optica (NMO) is an inflammatory disease associated with optic neuritis and myelitis. Although some studies have reported multiple sclerosis (MS)-like lesions in 10-30% of NMO patients, brain MRI is usually normal. Several studies have observed metabolic abnormalities on MR spectroscopy in MS, even in normal-appearing white matter (NAWM). To the authors' knowledge, MR spectroscopy has never been used to investigate NMO. The aim of this study was to evaluate metabolic abnormalities in the NAWM and normal-appearing grey matter (NAGM) of NMO patients. METHODS: The authors evaluated 24 patients (17 women and seven men, with a mean age of 44.6 years). NMO was diagnosed according to revised criteria. All patients had a brain and spinal cord MR imaging including MR spectroscopy sequences in both NAWM and NAGM. Patients were compared with 12 healthy subjects. RESULTS: NAA/creatinine ratios in NAWM (1.89 + or - 0.26 in NMO compared with 1.91 + or - 0.15 in control subjects) and NAGM (1.62 + or - 0.21 compared with 1.59 + or - 0.18) were normal, as were choline/creatinine ratios in NAWM (1.03 + or - 0.18 compared with 1.08 + or - 0.14) and NAGM (0.89 + or - 0.2 compared with 0.94 + or - 0.2). Myo-inositol values in NAWM were also normal (0.42 + or - 0.12 compared with 0.42 + or - 0.18). CONCLUSION: Our results are clearly different from those found in MS, where NAA is frequently decreased and choline increased, even in NAWM. Our findings could have an impact on the differentiation between MS and NMO.

Symptomatic paroxysmal dysarthria-ataxia in demyelinating diseases.

Paroxysmal dysarthria-ataxia syndrome (PDA) is a rare neurological disorder that can be either primary or symptomatic of acute neurological dysfunction. Episodes of symptomatic PDA are poorly documented and there are no video reports. We describe the cases of two patients with symptomatic PDA related to demyelinating diseases. Detailed studies of the patients' speech disorders showed that the dysarthria and gait disorders were of the ataxic type in both cases. Both patients had midbrain lesions at or below the level of the red nucleus, confirming that this area is critically involved in PDA. The best clinical signs for distinguishing between symptomatic and primary PDA are adult onset and short (<1 min) episodes in the former. If these signs are present, brain MRI should be used to identify a cause of symptomatic PDA.

Electrophysiological studies in a mouse model of Schwartz-Jampel syndrome demonstrate muscle fiber hyperactivity of peripheral nerve origin.

Schwartz-Jampel syndrome (SJS) is an autosomal-recessive condition characterized by muscle stiffness and chondrodysplasia. It is due to loss-of-function hypomorphic mutations in the HSPG2 gene that encodes for perlecan, a proteoglycan secreted into the basement membrane. The origin of muscle stiffness in SJS is debated. To resolve this issue, we performed an electrophysiological investigation of an SJS mouse model with a missense mutation in the HSPG2 gene. Compound muscle action potential amplitudes, distal motor latencies, repetitive nerve stimulation tests, and sensory nerve conduction velocities of SJS mice were normal. On electromyography (EMG), neuromyotonic discharges, that is, bursts of motor unit action potentials firing at high rates (120-300 HZ), were constantly observed in SJS mice in all muscles, except in the diaphragm. Neuromyotonic discharges were not influenced by general anesthesia and disappeared with curare administration. They persisted after complete motor nerve section, terminating only with Wallerian degeneration. These results demonstrate that perlecan deficiency in SJS provokes a neuromyotonic syndrome. The findings further suggest a distal axonal localization of the generator of neuromyotonic discharges. SJS should now be considered as an inherited disorder with peripheral nerve hyperexcitability.

Evidence of a dosage effect and a physiological endplate acetylcholinesterase deficiency in the first mouse models mimicking Schwartz-Jampel syndrome neuromyotonia.

Schwartz-Jampel syndrome (SJS) is a recessive neuromyotonia with chondrodysplasia. It results from hypomorphic mutations of the gene encoding perlecan, leading to a decrease in the levels of this heparan sulphate proteoglycan in basement membranes (BMs). It has been suggested that SJS neuromyotonia may result from endplate acetylcholinesterase (AChE) deficiency, but this hypothesis has never been investigated in vivo due to the lack of an animal model for neuromyotonia. We used homologous recombination to generate a knock-in mouse strain with one missense substitution, corresponding to a human familial SJS mutation (p.C1532Y), in the perlecan gene. We derived two lines, one with the p.C1532Y substitution alone and one with p.C1532Y and the selectable marker Neo, to down-regulate perlecan gene activity and to test for a dosage effect of perlecan in mammals. These two lines mimicked SJS neuromyotonia with spontaneous activity on electromyogramm (EMG). An inverse correlation between disease severity and perlecan secretion in the BMs was observed at the macroscopic and microscopic levels, consistent with a dosage effect. Endplate AChE levels were low in both lines, due to synaptic perlecan deficiency rather than major myofibre or neuromuscular junction disorganization. Studies of muscle contractile properties showed muscle fatigability at low frequencies of nerve stimulation and suggested that partial endplate AChE deficiency might contribute to SJS muscle stiffness by potentiating muscle force. However, physiological endplate AChE deficiency was not associated with spontaneous activity at rest on EMG in the diaphragm, suggesting that additional changes are required to generate such activity characteristic of SJS.