Axonal transport deficit in a KIF5A–/– mouse model

Hereditary spastic paraplegia (HSP) is a neurodegenerative disorder preferentially affecting the longest corticospinal axons. More than 40 HSP genetic loci have been identified, among them SPG10, an autosomal dominant HSP caused by point mutations in the neuronal kinesin heavy chain protein KIF5A. Constitutive KIF5A knockout (KIF5A–/–) mice die early after birth. In these mice, lungs were unexpanded, and cell bodies of lower motor neurons in the spinal cord swollen, but the pathomechanism remained unclear. To gain insights into the pathophysiology, we characterized survival, outgrowth, and function in primary motor and sensory neuron cultures from KIF5A–/– mice. Absence of KIF5A reduced survival in motor neurons, but not in sensory neurons. Outgrowth of axons and dendrites was remarkably diminished in KIF5A–/– motor neurons. The number of axonal branches was reduced, whereas the number of dendrites was not altered. In KIF5A–/– sensory neurons, neurite outgrowth was decreased but the number of neurites remained unchanged. In motor neurons maximum and average velocity of mitochondrial transport was reduced both in anterograde and retrograde direction. Our results point out a role of KIF5A in process outgrowth and axonal transport of mitochondria, affecting motor neurons more severely than sensory neurons. This gives pathophysiological insights into KIF5A associated HSP, and matches the clinical findings of predominant degeneration of the longest axons of the corticospinal tract

A Recurrent Mutation in KCNA2 as a Novel Cause of Hereditary Spastic Paraplegia and Ataxia

The hereditary spastic paraplegias (HSPs) are heterogeneous neurodegenerative disorders with over 50 known causative genes. We identified a recurrent mutation in KCNA2 (c.881G>A, p.R294H), encoding the voltage-gated K+-channel, K(V)1.2, in two unrelated families with HSP, intellectual disability (ID), and ataxia. Follow-up analysis of >2,000 patients with various neurological phenotypes identified a de novo p.R294H mutation in a proband with ataxia and ID. Two-electrode voltage-clamp recordings of Xenopus laevis oocytes expressing mutant KV1.2 channels showed loss of function with a dominant-negative effect. Our findings highlight the phenotypic spectrum of a recurrent KCNA2 mutation, implicating ion channel dysfunction as a novel HSP disease mechanism.Peer reviewe

Electrophysiological characterisation of motor and sensory tracts in patients with hereditary spastic paraplegia (HSP)

Background: Hereditary spastic paraplegias (HSPs) are characterised by lower limb spasticity due to degeneration of the corticospinal tract. We set out for an electrophysiological characterisation of motor and sensory tracts in patients with HSP. Methods: We clinically and electrophysiologically examined a cohort of 128 patients with genetically confirmed or clinically probable HSP. Motor evoked potentials (MEPs) to arms and legs, somato-sensory evoked potentials of median and tibial nerves, and nerve conduction studies of tibial, ulnar, sural, and radial nerves were assessed. Results: Whereas all patients showed clinical signs of spastic paraparesis, MEPs were normal in 27% of patients and revealed a broad spectrum with axonal or demyelinating features in the others. This heterogeneity can at least in part be explained by different underlying genotypes, hinting for distinct pathomechanisms in HSP subtypes. In the largest subgroup, SPG4, an axonal type of damage was evident. Comprehensive electrophysiological testing disclosed a more widespread affection of long fibre tracts involving peripheral nerves and the sensory system in 40%, respectively. Electrophysiological abnormalities correlated with the severity of clinical symptoms. Conclusions: Whereas HSP is primarily considered as an upper motoneuron disorder, our data suggest a more widespread affection of motor and sensory tracts in the central and peripheral nervous system as a common finding in HSP. The distribution patterns of electrophysiological abnormalities were associated with distinct HSP genotypes and could reflect different underlying pathomechanisms. Electrophysiological measures are independent of symptomatic treatment and may therefore serve as a reliable biomarker in upcoming HSP trials

Neurobiological correlates of emotional intelligence in voice and face perception networks

Facial expressions and voice modulations are among the most important communicational signals to convey emotional information. The ability to correctly interpret this information is highly relevant for successful social interaction and represents an integral component of emotional competencies that have been conceptualized under the term emotional intelligence. Here, we investigated the relationship of emotional intelligence as measured with the Salovey-Caruso-Emotional-Intelligence-Test (MSCEIT) with cerebral voice and face processing using functional and structural magnetic resonance imaging. MSCEIT scores were positively correlated with increased voice-sensitivity and gray matter volume of the insula accompanied by voice-sensitivity enhanced connectivity between the insula and the temporal voice area, indicating generally increased salience of voices. Conversely, in the face processing system, higher MSCEIT scores were associated with decreased face-sensitivity and gray matter volume of the fusiform face area. Taken together, these findings point to an alteration in the balance of cerebral voice and face processing systems in the form of an attenuated face-vs-voice bias as one potential factor underpinning emotional intelligence

De novo mutations in hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS).

OBJECTIVE: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is caused by autosomal-dominantly inherited mutations in the colony stimulating factor 1 receptor (CSF1R) gene, and is clinically characterized by a progressive cognitive and motor decline leading to death within several years. METHODS: In a continuous series of 25 patients with adult-onset leukoencephalopathy of unknown cause, we genetically confirmed HDLS in 6 families. Affected and nonaffected individuals were examined clinically and by brain MRI studies. RESULTS: HDLS presented as prominent dementia and apraxia, often with extrapyramidal and pyramidal signs, rarely with ataxia. White matter MRI changes were detectable early in the disease course. Family history was negative in 4 of 6 index patients. In 2 of 6 index patients, we could confirm the occurrence of de novo mutations in the CSF1R gene. One family showed possible incomplete penetrance: the 69-year-old father of the index patient carried a CSF1R mutation but was clinically unaffected. In one family, the parents were apparently unaffected and not available for genetic testing. CONCLUSIONS: Typical clinical phenotype and early brain MRI alterations can help to guide the diagnosis of HDLS. Because we confirmed de novo mutations in one-third of patients with CSF1R mutations, this diagnosis should be considered even in the absence of a family history. Furthermore, we present evidence for reduced penetrance of a CSF1R mutation. These results have substantial impact for genetic counseling of asymptomatic individuals at risk and should foster research into disease-modifying factors

Pure and syndromic optic atrophy explained by deep intronic OPA1 mutations and an intralocus modifier

The genetic basis of many optic neuropathies remains unclear. Bonifert et al. show that deep intronic OPA1 mutations can account for the disease in a number of previously unsolved cases. Moreover, an OPA1 modifier variant can generate syndromic 'optic atrophy plus' phenotypes if combined in trans with a loss-of-function OPA1 mutation.The genetic diagnosis in inherited optic neuropathies often remains challenging, and the emergence of complex neurological phenotypes that involve optic neuropathy is puzzling. Here we unravel two novel principles of genetic mechanisms in optic neuropathies: deep intronic OPA1 mutations, which explain the disease in several so far unsolved cases; and an intralocus OPA1 modifier, which explains the emergence of syndromic 'optic atrophy plus' phenotypes in several families. First, we unravelled a deep intronic mutation 364 base pairs 3' of exon 4b in OPA1 by in-depth investigation of a family with severe optic atrophy plus syndrome in which conventional OPA1 diagnostics including gene dosage analyses were normal. The mutation creates a new splice acceptor site resulting in aberrant OPA1 transcripts with retained intronic sequence and subsequent translational frameshift as shown by complementary DNA analysis. In patient fibroblasts we demonstrate nonsense mediated messenger RNA decay, reduced levels of OPA1 protein, and impairment of mitochondrial dynamics. Subsequent site-specific screening of > 360 subjects with unexplained inherited optic neuropathy revealed three additional families carrying this deep intronic mutation and a base exchange four nucleotides upstream, respectively, thus confirming the clinical significance of this mutational mechanism. Second, in all severely affected patients of the index family, the deep intronic mutation occurred in compound heterozygous state with an exonic OPA1 missense variant (p.I382M; NM_015560.2). The variant alone did not cause a phenotype, even in homozygous state indicating that this long debated OPA1 variant is not pathogenic per se, but acts as a phenotypic modifier if it encounters in trans with an OPA1 mutation. Subsequent screening of whole exomes from > 600 index patients identified a second family with severe optic atrophy plus syndrome due to compound heterozygous p.I382M, thus confirming this mechanism. In summary, we provide genetic and functional evidence that deep intronic mutations in OPA1 can cause optic atrophy and explain disease in a substantial share of families with unsolved inherited optic neuropathies. Moreover, we show that an OPA1 modifier variant explains the emergence of optic atrophy plus phenotypes if combined in trans with another OPA1 mutation. Both mutational mechanisms identified in this study-deep intronic mutations and intragenic modifiers-might represent more generalizable mechanisms that could be found also in a wide range of other neurodegenerative and optic neuropathy disease