DEPDC5 mutations in families presenting as autosomal dominant nocturnal frontal lobe epilepsy

Objective: To study the prevalence of DEPDC5 mutations in a series of 30 small European families with a phenotype compatible with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE).

Methods: Thirty unrelated families referred with ADNFLE were recruited in France, Italy, Germany, Belgium, and Norway. Whole-exome sequencing was performed in 10 probands and direct sequencing of the DEPDC5 coding sequence in 20 probands. Testing for nonsense-mediated messenger RNA decay (NMD) was performed in lymphoblastic cells.

Results: Exome sequencing revealed a splice acceptor mutation (c.2355-2A>G) in DEPDC5 in the proband of a German family. In addition, 3 nonsense DEPDC5 mutations (p.Arg487*, p.Arg1087*, and p.Trp1369*) were detected in the probands of 2 French and one Belgian family. The nonsense mutations p.Arg487* and p.Arg1087* were targeted by NMD, leading to the degradation of the mutated transcripts. At the clinical level, 78% of the patients with DEPDC5mutations were drug resistant.

Conclusions: DEPDC5 loss-of-function mutations were found in 13% of the families with a presentation of ADNFLE. The rate of drug resistance was high in patients with DEPDC5 mutations. Small ADNFLE pedigrees with DEPDC5mutations might actually represent a part of the broader familial focal epilepsy with variable foci phenotype.

Neurology 2014

Correlation of clinical and molecular features in spinal bulbar muscular atrophy

Objectives: To characterize the clinical and genetic features of spinal bulbar muscular atrophy (SBMA), a rare neurodegenerative disorder caused by the expansion of a CAG repeat in the first exon of the androgen receptor gene, in the United Kingdom.

Methods: We created a national register for SBMA in the United Kingdom and recruited 61 patients between 2005 and 2013. In our cross-sectional study, we assessed, by direct questioning, impairment of activities of daily living (ADL) milestones, functional rating, and subjective disease impact, and performed correlations with both CAG repeat size and degree of somatic mosaicism. Ten patients were deceased, 46 patients participated in the study, and 5 declined.

Results: Subjects had an average age at onset of 43.4 years, and weakness onset most frequently occurred in the lower limbs (87%). Impaired mobility was the most frequently reported problem by patients, followed by bulbar dysfunction. Age distribution of the impairment of ADL milestones showed remarkable overlap with a Japanese study. We have identified a significant correlation between the number of CAG repeats and both age at onset and ADL milestones. Somatic mosaicism also showed a correlation with CAG expansion size and age at onset.

Conclusions: Clinical features in SBMA show a substantial overlap when comparing populations with different genetic backgrounds. This finding has major implications, because multicenter trials will be necessary to obtain sufficient power in future clinical trials. Clinical-genetic correlations are strong in SBMA and should inform any clinical research strategy in this condition.

Neurology 2014

Voltage-gated sodium channel mutations and painful neuropathy: Nav1.9 joins the family

In its simplest terms neuropathic pain arises as a consequence of hyperexcitability within the somatosensory nervous system. It is not surprising therefore that voltage-gated sodium channels (VGSCs), with their key role in regulating neuronal excitability, have come to the fore as pathophysiological factors in human neuropathic pain states. Not only can mutations in these ion channels lead to altered impulse generation/conduction in sensory neurons but they may also lead to degeneration of axon terminals. The VGSC family of proteins has nine members, of which Na_v1.7, Na_v1.8 and Na_v1.9 (encoded by the genesSCN9A, SCN 10A and SCN 11A, respectively) are preferentially expressed in peripheral neurons (Eijkelkamp et al., 2012). While gain of function variants of Na_v1.7 and Na_v1.8 have previously been reported in patients with painful peripheral neuropathy, in this issue of Brain, Huang et al.(2014) present the first evidence for a causative role of missense mutations in Na_v1.9 in painful neuropathy.

Brain 2014

Gain-of-function mutations in sodium channel NaV1.9 in painful neuropathy

Sodium channel Na_v1.9 is expressed in peripheral nociceptive neurons, as well as visceral afferents, and has been shown to act as a threshold channel. Painful peripheral neuropathy represents a significant public health challenge and may involve gain-of-function variants in sodium channels that are preferentially expressed in peripheral sensory neurons. Although gain-of-function variants of peripheral sodium channels Na_v1.7 and Na_v1.8 have recently been found in painful small fibre neuropathy, the aetiology of peripheral neuropathy in many cases remains unknown. We evaluated 459 patients who were referred for possible painful peripheral neuropathy, and confirmed the diagnosis of small fibre neuropathy in a cohort of 393 patients (369 patients with pure small fibre neuropathy, and small fibre neuropathy together with large fibre involvement in an additional 24 patients). From this cohort of 393 patients with peripheral neuropathy, we sequenced SCN11A in 345 patients without mutations in SCN9A and SCN10A, and found eight variants in 12 patients. Functional profiling by electrophysiological recordings showed that these Na_v1.9 mutations confer gain-of-function attributes to the channel, depolarize resting membrane potential of dorsal root ganglion neurons, enhance spontaneous firing, and increase evoked firing of these neurons. Our data show, for the first time, missense mutations of Na_v1.9 in individuals with painful peripheral neuropathy. These genetic and functional observations identify missense mutations of Na_v1.9 as a cause of painful peripheral neuropathy.

Brain 2014

Feeling unreal: a functional imaging study in patients with Kleine-Levin syndrome

Kleine-Levin syndrome is characterized by relapsing-remitting episodes of severe hypersomnia, cognitive impairment, apathy, derealization and behavioural disturbances. Between episodes, patients have normal sleep, mood and behaviour. Functional imaging studies performed in small series of patients with Kleine-Levin syndrome with visual or semi-quantitative, uncontrolled analysis yielded equivocal brain changes. Using whole brain voxel-based group analysis, we compared brain perfusion scintigraphy during and between episodes in consecutive patients with Kleine-Levin syndrome versus healthy control subjects and correlated perfusion changes with disease severity and symptoms, focusing on less studied but disabling symptoms, such as apathy and derealization. During asymptomatic periods, 41 patients (mean age of 22.3 ± 8.1 years, 56.1% male) and 15 age- and sex-matched healthy control subjects underwent single-photon emission computed tomography scanning with technetium-99m ethyl cysteinate dimer. Eleven patients repeated the test during a symptomatic period. Compared with controls, patients during asymptomatic periods had persistent hypoperfusion in the hypothalamus, the thalamus (mainly the right posterior part), the caudate nucleus, and cortical associative areas, including the anterior cingulate, (Brodmann area 25), the orbito-frontal (Brodmann area 11) and the right superior temporal cortices (Brodmann area 22), extending to the insula (P < 0.001 in all area). Two additional hypoperfused areas emerged during symptomatic periods (P < 0.001), located in the right dorsomedial prefrontal cortex (Brodmann area 8) and the right parieto-temporal junction (Brodmann areas 22 and 39). These two areas were more affected between episodes, when the mean episode duration was longer (r = −0.53; P < 0.001). The score for the Depersonalization/Derealization Inventory during symptomatic periods strongly correlated with the hypoperfusion of the right (r = −0.74, P < 0.001) and left (r = −0.59, P <0.005) parieto-temporal junctions. No hyperperfusion was found. Because the parieto-temporal junction (including the angular gyrus) is involved in cross-modal association between somatosensory (body knowledge), auditory and visual information, the robust hypoperfusions and correlations observed in this area may underlie the striking derealization reported by patients during episodes. Defects in the dorsomedial prefrontal cortex may cause apathy. Persistent hypoperfusion in the diencephalic and associative cortical area during asymptomatic periods is a marker of the disease, suggestive of a scenario wherein patients compensate for these deficient circuitries.

Brain 2014

Hypomyelination with atrophy of the basal ganglia and cerebellum: further delineation of the phenotype and genotype–phenotype correlation

Hypomyelination with atrophy of the basal ganglia and cerebellum is a rare leukoencephalopathy that was identified using magnetic resonance imaging in 2002. In 2013, whole exome sequencing of 11 patients with the disease revealed that they all had the same de novo mutation inTUBB4A, which encodes tubulin β-4A. We investigated the mutation spectrum in a cohort of 42 patients and the relationship between genotype and phenotype. Patients were selected on the basis of clinical and magnetic resonance imaging abnormalities that are indicative of hypomyelination with atrophy of the basal ganglia and cerebellum. Genetic testing and a clinical inventory were performed, and sequential magnetic resonance images were evaluated using a standard protocol. The heterozygous TUBB4A mutation observed in the first 11 patients was the most common (25 patients). Additionally, 13 other heterozygous mutations were identified, located in different structural domains of tubulin β-4A. We confirmed that the mutations were de novo in all but three patients. In two of these three cases we lacked parental DNA and in one the mutation was also found in the mother, most likely due to mosaicism. Patients showed a phenotypic continuum ranging from neonatal to childhood disease onset, normal to delayed early development and slow to more rapid neurological deterioration. Neurological symptomatology consisted of extrapyramidal movement abnormalities, spasticity, ataxia, cognitive deficit and sometimes epilepsy. Three patients died and the oldest living patient was 29 years of age. The patients’ magnetic resonance images showed an absent or disappearing putamen, variable cerebellar atrophy and highly variable cerebral atrophy. Apart from hypomyelination, myelin loss was evident in several cases. Three severely affected patients had similar, somewhat atypical magnetic resonance image abnormalities. The study results were strongly suggestive of a genotype–phenotype correlation. The 25 patients with the common c.745G>A mutation generally had a less rapidly progressive disease course than the 17 cases with other TUBB4A mutations. Overall, this work demonstrates that the distinctive magnetic resonance imaging pattern for hypomyelination with atrophy of the basal ganglia and cerebellum defines a homogeneous clinical phenotype of variable severity. Patients almost invariably have prominent extrapyramidal movement abnormalities, which are rarely seen in patients with hypomyelination of different origin. A dominant TUBB4A mutation is also associated with dystonia type 4, in which magnetic resonance images of the brain seem normal. It is highly likely that there is a disease continuum associated withTUBB4A mutations, of which hypomyelination with atrophy of the basal ganglia and cerebellum and dystonia type 4 are the extremes. This would indicate that extrapyramidal movement abnormalities constitute the core feature of the disease spectrum related to dominant TUBB4A mutations and that all other features are variable

Brain 2014

Ischaemic stroke in young adults: risk factors and long-term consequences

Contrary to trends in most other diseases, the average age of ischaemic stroke onset is decreasing, owing to a rise in the incidence of stroke among 'young' individuals (under 50 years of age). This Review provides a critical overview of the risk factors and aetiology of young ischaemic stroke and addresses its long-term prognosis, including cardiovascular risk, functional outcome and psychosocial consequences. We highlight the diminishing role of 'rare' risk factors in the pathophysiology of young stroke in light of the rising prevalence of 'traditional' vascular risk factors in younger age groups. Long-term prognosis is of particular interest to young patients, because of their long life expectancy and major responsibilities during a demanding phase of life. The prognosis of young stroke is not as favourable as previously thought, with respect either to mortality or cardiovascular disease or to psychosocial consequences. Therefore, secondary stroke prevention is probably a life-long endeavour in most young stroke survivors. Due to under-representation of young patients in past trials, new randomized trials focusing on this age group are needed to confirm the benefits of long-term secondary preventive medication. The high prevalence of poor functional outcome and psychosocial problems warrants further study to optimize treatment and rehabilitation for these young patients.

Nature Reviews Neurology 2014