Genetic origin of a large family with a novel PSEN1 mutation (Ile416Thr)

IntroductionA small percentage of Alzheimer's disease (AD) cases are caused by genetic mutations with autosomal dominant inheritance. We report a family with a novel variant in PSEN1.MethodsWe performed clinical and genetic evaluation of 93 related individuals from a Colombian admixed population. 31 individuals had whole-genome sequencing.ResultsGenetic analysis revealed a missense variant in PSEN1 (NM_000021.3: c.1247T>C p.Ile416Thr), which originated on an African haplotype and segregated with AD logarithm of the odds score of 6. Their clinical phenotype is similar to sporadic AD except for earlier age at onset: the mean age at onset for mild cognitive impairment was 47.6 years (standard deviation 5.83) and for dementia 51.6 years (standard deviation 5.03).DiscussionIle416Thr is a novel pathogenic variant that causes AD in the sixth decade of life. The history of the region that included slave importation and admixtures within a confined geographic locale represents a “mini-population bottleneck” and subsequent emergence of a rare dominant mutation.     

Two mild cases of Dravet syndrome with truncating mutation of SCN1A

Background

SCN1A is the gene that codes for the neuronal voltage-gated sodium-channel alpha-subunit 1. It is generally considered that an SCN1A truncating mutation causes the severe phenotype of Dravet syndrome.

Jargon dyslexia in an individual with semantic dementia: Further evidence for task-specificity in phonological output

We report a patient with semantic dementia who demonstrated a very unusual dyslexia. He had a global loss of conceptual knowledge in the context of a fluent dysphasia and intact syntax. However, he did not have the surface dyslexia which is typical of semantic dementia; rather his reading impairment was characterized by speech production errors resulting in multiple neologisms. In a series of experiments it was established that input phonological and input orthographical processing were intact as was output phonology for naming and propositional speech. We demonstrate that our patient has a task-specific phonological deficit and we argue that reading and propositional speech rely upon dissociable phonological output systems. Thus we corroborate our earlier evidence of task-specific phonological output stores (Crutch and Warrington, 2001 Crutch, SJ and Warrington, EK. 2001. Refractory dyslexia: Evidence of multiple task-specific phonological output stores. Brain, 124: 1533–1543. [PUBMED][INFOTRIEVE][CSA][CROSSREF] [Google Scholar]). We also document a greater difficulty with comprehending the written than the spoken word. We account for this pattern of performance in terms of our patient’s attempting to read by the indirect phonological route, as with other semantic dementia patients, but suggest that this process is overridden by the task-specific speech production deficit.     

Generation of a human induced pluripotent stem cell–based model for tauopathies combining three microtubule-associated protein TAU mutations which displays several phenotypes linked to neurodegeneration

Introduction

Tauopathies are neurodegenerative diseases characterized by TAU protein–related pathology, including frontotemporal dementia and Alzheimer's disease among others. Mutant TAU animal models are available, but none of them faithfully recapitulates human pathology and are not suitable for drug screening.

Successful treatment of normokalemic periodic paralysis with hydrochlorothiazide

Background

Periodic paralysis (PP) is an autosomal dominant muscle disorder characterized by periodic muscle weakness attacks associated with serum potassium level variations. It is classified into hypokalemic (hypoKPP), hyperkalemic (hyperKPP), and normokalemic (normoKPP) forms based on the ictal serum potassium level. HyperKPP and normoKPP are caused by mutations of the same gene SCN4A, the gene encoding the skeletal muscle voltage-gated sodium channel. Prophylactic treatment with thiazide diuretics is highly effective in preventing attacks in hyperKPP. However, the efficacy and safety of such diuretics in normoKPP remain unclear.

Mayo's Older Americans Normative Studies: Age- and IQ-Adjusted Norms for the Wechsler Memory Scale--Revised

ABSTRACT

Normative data sets for standardized neuropsychometric instruments often include adjustments for subject variables. There are reasons to believe, however, that improvements in interpretive accuracy that result from such adjustments are less than optimal. In particular, “years of formal education” may be less closely related to test performances than is general intellectual functioning. In this third of four reanalyses of results from the Mayo Clinic's Older Americans Normative Studies (MOANS) databases, age-adjusted index and scaled scores for the Wechsler Memory Scale-Revised were found to be more strongly associated with Mayo age-adjusted WAIS-R Full Scale IQ scores (rs = .271 to .631) than with education (rs = .089 to .310) for healthy older examinees between 56 and 99 years of age. These associations were strongest for Attention/Concentration and General Memory Index scores and, in general, for individuals with average intelligence (cf. Dodrill, 1997 Dodrill , C. B. ( 1997 ). Myths of neuropsychology . The Clinical Neuropsychologist , 11 , 1 – 17 .[Taylor & Francis Online], [Web of Science ®] , [Google Scholar] 1999 Dodrill , C. B. ( 1999 ). Myths of neuropsychology: Further considerations . The Clinical Neuropsychologist , 13 , 562 – 572 . [PUBMED] [INFOTRIEVE] [CSA] [Taylor & Francis Online], [Web of Science ®] , [Google Scholar]). Tables of age- and IQ-adjusted percentile equivalents of Mayo age-adjusted WMS-R index scores and MOANS age-adjusted WMS-R subtest scaled scores are presented for eleven age ranges and seven IQ ranges.     

Mayo's Older Americans Normative Studies: Age- and IQ-Adjusted Norms for the Auditory Verbal Learning Test and the Visual Spatial Learning Test

ABSTRACT

Although normative data sets for standardized neuropsychometric instruments frequently feature adjustments for subject variables, there are reasons to believe that improvements in interpretive accuracy that result from such adjustments are less than optimal. In particular, years of education may be less closely associated with test performances than is overall intellectual functioning. In this last of four reanalyses of results from the Mayo Clinic's Older Americans Normative Studies (MOANS) databases, age-adjusted scores for the Rey Auditory Verbal Learning Test and the Visual Spatial Learning Test were found to be more strongly related to Mayo age-adjusted WAIS-R Full Scale IQ scores (rs = .150 to .395) than to education (rs = .060 to .236) for healthy older examinees between 56 and 99 years of age. Although AVLT-FSIQ correlations were greatest at moderate levels of intelligence, VSLT-FSIQ correlations consistently increased in strength as intelligence increased (cf. Dodrill, 1997 Dodrill , C. B. ( 1997 ). Myths of neuropsychology . The Clinical Neuropsychologist , 11 , 1 – 17 .[Taylor & Francis Online], [Web of Science ®] , [Google Scholar] 1999 Dodrill , C. B. ( 1999 ). Myths of neuropsychology: Further considerations . The Clinical Neuropsychologist , 13 , 562 – 572 . [PUBMED] [INFOTRIEVE] [CSA] [Taylor & Francis Online], [Web of Science ®] , [Google Scholar]). Based on these results, we present tables of age- and IQ-adjusted percentile equivalents of Mayo age-adjusted AVLT index scores and MOANS age-adjusted AVLT and VSLT scaled scores for ten age ranges and either seven (AVLT) or five (VSLT) IQ ranges.     

Severe myoclonic epilepsy of infancy (Dravet syndrome): Clinical and genetic features of nine Turkish patients

Purpose:

Mutations of the α-1 subunit sodium channel gene (SCN1A) cause severe myoclonic epilepsy of infancy (SMEI). To date, over 300 mutations related to SMEI have been described. In the present study, we report new SCN1A mutations and the clinical features of SMEI cases.

Materials and Methods:

We studied the clinical and genetic features of nine patients diagnosed with SMEI at the Pediatric Neurology Department of Istanbul Medical Faculty.

Results:

Five patients had nonsense mutations, two had missense mutations, one had a splice site mutation and one had a deletion mutation of the SCN1A gene. Mutations at c.3705+5G splice site, p.trip153X nonsense mutation and deletion at c.2416_2946 have not been previously described. The seizures started following whole cell pertussis vaccination in all patients. The seizures ceased in one patient and continued in the other eight patients. Developmental regression was severe in three patients, with frequent status epilepticus. The type of mutation was not predictive for the severity of the disease. Two of the three patients with severe regression had nonsense and missense mutations.

Conclusions:

Dravet syndrome can be result of several different types of mutation in SCN1A gene. Onset of the seizures after pertussis vaccination is an important clue for the diagnosis and neuro- developmental delay should be expected in all patients.     

Clinical Diversity of SCN4A-Mutation-Associated Skeletal Muscle Sodium Channelopathy

Background and Purpose

Mutations of the skeletal muscle sodium channel gene SCN4A, which is located on chromosome 17q23-25, are associated with various neuromuscular disorders that are labeled collectively as skeletal muscle sodium channelopathy. These disorders include hyperkalemic periodic paralysis (HYPP), hypokalemic periodic paralysis, paramyotonia congenita (PMC), potassium-aggravated myotonia, and congenital myasthenic syndrome. This study analyzed the clinical and mutational spectra of skeletal muscle sodium channelopathy in Korean subjects.

Methods

Six unrelated Korean patients with periodic paralysis or nondystrophic myotonia associated with SCN4A mutations were included in the study. For the mutational analysis of SCN4A, we performed a full sequence analysis of the gene using the patients'' DNA. We also analyzed the patients'' clinical history, physical findings, laboratory tests, and responses to treatment.

Results

We identified four different mutations (one of which was novel) in all of the patients examined. The novel heterozygous missense mutation, p.R225W, was found in one patient with mild nonpainful myotonia. Our patients exhibited various clinical phenotypes: pure myotonia in four, and PMC in one, and HYPP in one. The four patients with pure myotonia were initially diagnosed as having myotonia congenita (MC), but a previous analysis revealed no CLCN1 mutation.

Conclusions

Clinical differentiating between sodium-channel myotonia (SCM) and MC is not easy, and it is suggested that a mutational analysis of both SCN4A and CLCN1 is essential for the differential diagnosis of SCM and MC.     

Novel RAB3GAP1 Mutation in the First Tunisian Family With Warburg Micro Syndrome

Background and PurposeWarburg Micro syndrome (WARBM) is a rare autosomal recessive genetic disease characterized by ocular, neurologic, and endocrine anomalies. WARBM is a phenotypically and genetically heterogeneous syndrome caused by mutations in RAB3GAP1, RAB3GAP2, RAB18, and TBC1D20. Here we present the clinical and genetic characterization of a consanguineous Tunisian family with a WARBM phenotype presenting two pathogenic variations, one of which is on RAB3GAP1.MethodsWe applied whole-exome sequencing (WES) to two affected young males presenting a WARBM-compatible phenotype.ResultsWe reveal a new variation in RAB3GAP1 ({"type":"entrez-nucleotide","attrs":{"text":"NM_012233.3","term_id":"1677500243"}}NM_012233.3: c.297del, p.Gln99fs) and another variation in ABCD1 ({"type":"entrez-nucleotide","attrs":{"text":"NM_000033","term_id":"1519313321"}}NM_000033: c.896A>G, p.His299Arg). Each of these mutations, which in silico predictions concluded as being pathogenic variations, affects a critical protein region. Both affected males presented a WARBM-compatible phenotype, with severe intellectual disability, severe developmental delay, postnatal growth delay, postnatal microcephaly, congenital bilateral cataracts, general hypotonia, and a thin corpus callosum without a splenium. However, intrafamilial clinical heterogeneity was present, since only the oldest child had large ears, microphthalmia, foot deformities, and a genital anomaly, and only the youngest child had microcornea. Despite the mutation identified in ABCD1, our patients did not have any X-linked symptoms of adrenoleukodystrophy disorder that are usually caused by ABCD1 mutations, which prompted our interest in clinical monitoring.ConclusionsWES analysis of a consanguineous Tunisian family with WARBM revealed a novel variation in RAB3GAP1 ({"type":"entrez-nucleotide","attrs":{"text":"NM_012233.3","term_id":"1677500243"}}NM_012233.3: c.297del, p.Gln99fs) that is most likely pathogenic and allowed us to confirm the diagnosis of WARBM.     

Type-D Personality Can Predict Suicidality in Patients with Major Depressive Disorder

Objective

This study investigated the putative association between type-D personality and suicidality, including the history of suicide attempt and suicidal ideation in patients with major depressive disorder (MDD).

Methods

Eighty-six outpatients aged between 18 and 65 years with MDD were recruited for this study from Ilsan Paik Hospital. The cohort was stratified into two subgroups according to the presence of type-D personality and history of suicide attempt (yes vs. no). Depression severity was evaluated using the Hamilton Depression Rating Scale. The type-D Personality Scale-14 (DS-14), the Beck Hopelessness Scale (BHS), the Barratt Impulsiveness Scale (BIS), the Hamilton Anxiety Scale, and the Beck Scale for Suicidal Ideation (BSS) were also applied.

Results

The total BSS, BHS, and BIS scores were higher for the group with type-D personality than for the group without this personality (p=0.004, 0.01, and 0.003, respectively). In addition, the total scores for the BSS, BHS, and social inhibition (SI; subscale of DS-14) were higher for the group with a history of suicide attempt than for the group without this history (p=0.0000004, 0.003, and 0.033, respectively). There were positive correlations between the total DS-14 score and the total BSS, BHS, and BIS scores (r=0.413 and p=0.000077, r=0.404 and p=0.00012, and r=0.245 and p=0.024, respectively).

Conclusion

Depressed patients with type-D personality are more vulnerable to suicidality than those without type-D personality, even when the MDD severity is identical. In addition, the SI score was higher in patients with a history of suicide attempt than in those without this history.     

SCN8A as a novel candidate gene associated with bipolar disorder in the Han Chinese population

Background

Bipolar disorder (BPD) is a common, severe and recurrent psychiatric disorder. It has been suggested that BPD patients have a higher risk of suicide than patients with any other psychiatric illnesses. A recent study found that suicide attempt was associated with the SCN8A gene, which has been mapped close to one of the BPD susceptibility loci. Thus, SCN8A is likely to be a candidate gene for BPD.

Methods

In this study, three SNPs (rs1601012, rs303810, rs60637) were analyzed in 506 bipolar patients and 507 controls of Han origin.

Results

We found that two individual SNPs showed statistically significant differences between cases and controls in both allele and genotype distribution, but only rs303810 was still significant in allele distribution (p = 0.0164) after correction. No obvious linkage disequilibrium or haplotypes were observed among these SNPs.

Conclusion

Our results indicate that SCN8A may be a potential susceptibility gene for bipolar disorder in the Han Chinese population.     

Knowledge of living,nonliving and “sensory quality” categories in semantic dementia

This article reports the findings from 3 patients with semantic dementia (SD) who were given a novel battery of 33 items from sensory quality categories (SQCs) as previously described by Borgo and Shallice (2001 Borgo, F and Shallice, T. 2001. When living things and other "sensory quality" categories behave in the same fashion: A novel category specificity effect. Neurocase, 7: 201–220. [PUBMED][INFOTRIEVE][CSA][CROSSREF][Taylor & Francis Online], [Web of Science ®] , [Google Scholar]; 2003) and Laiacona, Capitani and Caramazza (2003) Laiacona, M, Capitani, E and Caramazza, A. 2003. Category-specific semantic deficits do not reflect the sensory/functional organisation of the brain: A test of the “sensory quality” hypothesis. Neurocase, 9(3): 221–231. [PUBMED][INFOTRIEVE][CSA][CROSSREF][Taylor & Francis Online], [Web of Science ®] , [Google Scholar]. Their performance on three tasks (two naming, one word-to-picture matching) was compared with performance on similar tasks using a conventional semantic battery. At the group level, patients performed worse than age-matched controls overall, but neither group showed any differences in performance between domains (i.e., living, nonliving and SQCs). Individual patient analyses, however, showed contrasting profiles in the three patients. The results are discussed in terms of the SFT (Warrington & Shallice, 1984 Warrington, EK and Shallice, T. 1984. Category specific semantic impairments. Brain, 107: 829–854. [PUBMED][INFOTRIEVE][CSA][Crossref], [PubMed], [Web of Science ®] , [Google Scholar]) and individual differences (Lambon-Ralph et al., 2003) accounts of category-specificity in SD.     

Behavioral and electrophysiological evidence for GABAergic modulation through transcutaneous vagus nerve stimulation

Objective

Transcutaneous vagus nerve stimulation (tVNS) has been hypothesized to modulate γ-aminobutyric (GABA) transmission in the human brain. GABA in the motor cortex is highly correlated to measures of automatic motor inhibition that can be obtained in simple response priming paradigms. To test the effects of tVNS on GABA transmission, we measured tVNS-induced alterations in behavioral and electrophysiology during automatic motor inhibition.

Remarkable Phenytoin Sensitivity in 4 Children with SCN8A-related Epilepsy: A Molecular Neuropharmacological Approach

Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation.

Electronic supplementary material

The online version of this article (doi:10.1007/s13311-015-0372-8) contains supplementary material, which is available to authorized users.Key Words: SCN8A, phenytoin, epileptic encephalopathy, sodium channel blockers     

Mayo's Older Americans Normative Studies: Age- and IQ-Adjusted Norms for the Boston Naming Test,the MAE Token Test,and the Judgment of Line Orientation Test

ABSTRACT

Although many extant normative data sets for standardized neuropsychometric instruments feature adjustments for subject variables, there are reasons to believe that improvements in interpretive accuracy that result from such adjustments are less than optimal. In particular, several theoretical considerations suggest that years of formal education may be less closely related to test performances than is general intellectual functioning. In this first of four reanalyses of results from the Mayo Clinic's Older Americans Normative Studies (MOANS) databases, age-adjusted scores on the Boston Naming Test, the MAE Token Test, and the Judgment of Line Orientation Test were indeed found to be more strongly associated with Mayo Age-adjusted WAIS-R Full Scale IQ scores (rs = .608, .473, and .502, respectively) than with education (rs = .310, .306, and .236, respectively) for healthy older examinees (56–99 years). Consistent with the remarks of Dodrill (1997 Dodrill , C. B. ( 1997 ). Myths of neuropsychology . The Clinical Neuropsychologist , 11 , 1 – 17 .[Taylor & Francis Online], [Web of Science ®] , [Google Scholar] 1999 Dodrill , C. B. ( 1999 ). Myths of neuropsychology: Further considerations . The Clinical Neuropsychologist , 13 , 562 – 572 . [PUBMED] [INFOTRIEVE] [CSA] [Taylor & Francis Online], [Web of Science ®] , [Google Scholar]), these correlations generally decreased at higher levels of intelligence. The magnitude and pattern of such declines varied across the three tests, however, suggesting that IQ-test score associations must be empirically determined rather than assumed to be linear. Tables of Age- and IQ-Adjusted percentile equivalents of MOANS Age-adjusted BNT, Token Test, and JLO scaled scores are presented for eleven age ranges and seven IQ ranges. The article concludes with a discussion of factors that may underlie observed relations among age, intelligence, and neuropsychometric test performances.     

Motor cortex excitability in seizure-free STX1B mutation carriers with a history of epilepsy and febrile seizures

Objective

Mutations in STX1B encoding the presynaptic protein syntaxin-1B are associated with febrile seizures with or without epilepsy. It is unclear to what extent these mutations are linked to abnormalities of cortical glutamatergic or GABAergic neurotransmission. We explored this question using single- and paired-pulse transcranial magnetic stimulation (TMS) excitability markers.