Bilateral Pallidal Stimulation in a Family With Myoclonus Dystonia Syndrome Due to a Mutation in the Sarcoglycan Gene

ObjectivesThe study aimed to present a family with myoclonus dystonia (M-D) syndrome due to a mutation in the epsilon sarcoglycan gene (SGCE). Three members of the family suffered from treatment-refractory severe myoclonic jerks of the neck, trunk, and upper extremities. The mild dystonic symptoms recognized as cervical dystonia or truncal dystonia affected all individuals. The efficacy of pharmacotherapy, including anticholinergic, dopaminergic, and serotoninergic drugs, has failed. One individual developed an alcohol dependency and suffered from alcoholic epilepsy.Materials and MethodsThe patients were referred for stereotactic surgery. All individuals underwent bilateral implantation of deep brain stimulation (DBS) leads into the posteroventrolateral segment of the globus pallidus internus (GPi). Surgeries were uneventful. The formal preoperative objective assessment included the Unified Myoclonus Rating Scale (UMRS) and the Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS). The postoperative UMRS and BFMDRS assessments were done only under continuous stimulation at 3, 6, and 12 months after the surgery and at the last available follow-up ranging from 6 to 15 months (mean, 10 months follow-up).ResultsAt the last follow-up visit, the rest and action parts of UMRS were improved by 93.3% and 88.2%, respectively, when compared to the baseline scores. The motor and disability scales of BFMDRS were improved by 77% and 43% at the last follow-up visit compared to the baseline BFMDRS scores. There were no hardware or stimulation-induced complications over the follow-up period. Positive social adjustment allowed two patients to regain jobs and one patient continued his education and hobbies.ConclusionOur experience gathered in three individuals in the family with a mutation in SGCE indicates that bilateral GPi DBS can be an effective and safe treatment for disabling pharmacological resistant, intractable M-D syndrome.     

Identification of a Novel Mutation in the Presenilin 1 Gene in a Chinese Alzheimer’s Disease Family

This study has identified a gene mutation in a Chinese family with Alzheimer’s disease (AD). Family members were screened by a set of medical examinations and neuropsychological tests. Their DNA was extracted from blood cells and sequenced for gene mutation in the amyloid precursor protein (APP), the presenilin 1 (PS1) and the presenilin 2 (PS2) genes. Genetic analysis showed that the AD patients in the family harbored a T to G missense mutation at the position 314 in exon 4 of the PS1 gene, resulting in a change of F105C in amino acid sequence. Clinical manifestation of these patients included memory loss, counting difficulty, personality change, disorientation, dyscalculia, agnosia, aphasia, and apraxia, which was similar to that of the familial AD (FAD) patients harboring other PS1 mutations. We intend to add a novel mutation F105C of the PS1 gene to the pool of FAD mutations. With the current available genetic data, mutations of the PS1 gene account for the majority of gene mutations in Chinese FAD.     

Does the Co-occurrence of FGFR3 Gene Mutation in Hypochondroplasia,Medial Temporal Lobe Dysgenesis,and Focal Epilepsy Suggest a Syndrome?

BackgroundHypochondroplasia is a rare skeletal dysplasia characterized by disproportionately short stature, lumbar lordosis, and limited extension of the elbow caused by mutations in the fibroblast growth factor receptor 3 (FGFR3) gene that plays a role in controlling nervous system development. Hypochondroplasia with FGFR3 mutation associated with bilateral medial temporal lobe anomalies and focal epilepsy was previously reported in several patients.PatientWe report clinical, electroclinical, and neuroradiological findings of one patient affected by hypochondroplasia.ResultsClinical diagnosis was confirmed by molecular analysis of the FGFR3 gene, which showed a N540 K mutation. The patient had normal psychomotor development and showed early-onset focal seizures with left temporal localization on interictal and ictal electroencephalograph. The seizures were well controlled, and the patient has been seizure-free since infancy. Magnetic resonance imaging showed abnormal anteriorly posteriorly infolding in the hippocampus and abnormally oriented parahippocampus sulci, and additional cortical rim dysplasia with gray-white matter junction blurring in the hippocampus.ConclusionsThe present case of hypochondroplasia and FGFR3 mutation in Asn540Lys associated with characteristic abnormalities involving bilaterally medial temporal lobe structures, probable hippocampal cortex focal dysplasia, and early onset of focal epilepsy underscores the possibility of a rare syndrome.     

Temporal–occipital glioblastoma presenting with Alice in Wonderland Syndrome in a patient with a long-time history of migraine without aura

ABSTRACT

Alice in Wonderland Syndrome (AIWS) is a rare perceptual disorder characterized by an erroneous perception of the body or the surrounding space. AIWS may be caused by different pathologies, ranging from infections to migraine. We present the case of a 54-year-old man, with a long-time history of migraine without aura, diagnosed with AIWS due to a glioblastoma located in the left temporal–occipital junction. To date, this is the first case of AIWS caused by glioblastoma. This case suggests that to exclude aura-mimic phenomena, a careful diagnostic workup should always be performed even in patients with a long-time history of migraine.     

Fragile X Syndrome Patient–Derived Neurons Developing in the Mouse Brain Show FMR1-Dependent Phenotypes

BackgroundFragile X syndrome (FXS) is characterized by physical abnormalities, anxiety, intellectual disability, hyperactivity, autistic behaviors, and seizures. Abnormal neuronal development in FXS is poorly understood. Data on patients with FXS remain scarce, and FXS animal models have failed to yield successful therapies. In vitro models do not fully recapitulate the morphology and function of human neurons.MethodsTo mimic human neuron development in vivo, we coinjected neural precursor cells derived from FXS patient–derived induced pluripotent stem cells and neural precursor cells derived from corrected isogenic control induced pluripotent stem cells into the brain of neonatal immune-deprived mice.ResultsThe transplanted cells populated the brain and a proportion differentiated into neurons and glial cells. Immunofluorescence and single and bulk RNA sequencing analyses showed accelerated maturation of FXS neurons after an initial delay. Additionally, we found increased percentages of Arc- and Egr-1–positive FXS neurons and wider dendritic protrusions of mature FXS striatal medium spiny neurons.ConclusionsThis transplantation approach provides new insights into the alterations of neuronal development in FXS by facilitating physiological development of cells in a 3-dimensional context.     

Neurophysiological Studies and Non-Motor Symptoms Prior to Ataxia in a Patient with Machado–Joseph Disease: Trying to Understand the Natural History of Brain Degeneration

Spinocerebellar ataxia type 3 or Machado–Joseph disease is the most common spinocerebellar ataxia. In this neurological disease, anatomical, physiological, clinical, and functional neuroimaging demonstrate a degenerative process besides the cerebellum. We performed neurophysiological and neuroimaging studies—polysomnography, transcranial sonography, vestibular-evoked myogenic potential, single-photon emission computed tomography (SPECT) with ^99mTc-TRODAT-1, and a formal neuropsychological evaluation in a patient with sleep complaints and positive testing for Machado–Joseph disease, without cerebellar atrophy, ataxia, or cognitive complaints. Polysomnography disclosed paradoxical high amplitude of submental muscle, characterizing REM sleep without atonia phenomenon. Transcranial sonography showed hyperechogenicity of the substantia nigra. There was an absence of vestibular-evoked myogenic potentials on both sides in the patient under study, in opposite to 20 healthy subjects. Brain imaging SPECT with ^99mTc-TRODAT-1 demonstrated a significant lower DAT density than the average observed in six healthy controls. Electroneuromyography was normal. Neuropsychological evaluation demonstrated visuospatial and memory deficits. Impairment of midbrain cholinergic and pontine noradrenergic systems, dysfunction of the pre-synaptic nigrostriatal system, changes in echogenicity of the substantia nigra, and damage to vestibulo-cervical pathways are supposed to occur previous to cerebellar involvement in Machado–Joseph disease.     

A Novel Mutation of the CLN8 Gene: Is There a Mediterranean Phenotype?

We report the first known case in Israel of a patient with an early childhood onset of ceroid-lipofuscinosis who is homozygous to a mutation of the CLN8 gene. This patient further expands the clinical varieties of CLN8, initially reported in Finland and Turkey and recently in Italy. The ultrastructural pathology of a skin biopsy specimen revealed abundant typical fingerprint profiles, but rare granular osmiophilic bodies and curvilinear structures. Sequencing of exon 3 of the CLN8 gene revealed a novel C>G missense mutation at a conserved amino acid glutamine 256 to glutamic acid. Our findings further raise the possibility of the existence of a Mediterranean CLN8 variant.     

Validation of the Patient Health Questionnaire–9 and Patient Health Questionnaire–2 in the General Korean Population

ObjectiveThe Patient Health Questionnaire–9 (PHQ-9) and PHQ-2 have not been validated in the general Korean population. This study aimed to validate and identify the optimal cutoff scores of the PHQ-9 and PHQ-2 in screening for major depression in the general Korean population.MethodsWe used data from 6,022 participants of the Korean Epidemiological Catchment Area Study for Psychiatric Disorders in 2011. Major depression was diagnosed according to the Korean Composite International Diagnostic Interview. Validity, reliability, and receiver operating characteristic curve analyses were performed using the results of the PHQ-9 and Euro Quality of life-5 dimension (EQ-5d).ResultsOf the 6,022 participants, 150 were diagnosed with major depression (2.5%). Both PHQ-9 and PHQ-2 demonstrated relatively high reliability and their scores were highly correlated with the “anxiety/depression” score of the EQ-5d. The optimal cutoff score of the PHQ-9 was 5, with a sensitivity of 89.9%, specificity of 84.1%, positive predictive value (PPV) of 12.6%, negative predictive value (NPV) of 99.7%, positive likelihood ratio (LR+) of 5.6, and negative likelihood ratio (LR-) of 0.12. The optimal cutoff score of the PHQ-2 was 2, with a sensitivity of 85.3%, specificity of 83.2%, PPV of 11.6%, NPV of 99.5%, LR+ of 5.1, and LR- of 0.18.ConclusionThe PHQ-9 and PHQ-2 are valid tools for screening major depression in the general Korean population, with suggested cutoff values of 5 and 2 points, respectively.     

New findings in the ataxia of Charlevoix–Saguenay

The aim of the study was to enhance our understanding of the pathogenesis of the ataxia of Charlevoix-Saguenay, based on the findings presented herein. Five patients with a molecular diagnosis of this disease underwent clinical, radiological, ophthalmologic and electrophysiological examinations. Five novel mutations, which included nonsense and missense variants, were identified, with these resulting in milder phenotypes. In addition to the usual manifestations, a straight dorsal spine was found in every case, and imaging techniques showed loss of the dorsal kyphosis. Cranial MRI demonstrated hypointense linear striations at the pons. Tensor diffusion MRI sequences revealed that these striations corresponded with hyperplastic pontocerebellar fibres, and tractographic sequences showed interrupted pyramidal tracts at the pons. Ocular coherence tomography demonstrated abnormal thickness of the nerve fibre layer. Electrophysiological studies showed nerve conduction abnormalities compatible with a dysmyelinating neuropathy, with signs of chronic denervation in distal muscles. The authors suggest that the hyperplastic pontocerebellar fibres compress the pyramidal tracts at the pons, and that the amount of retinal fibres traversing the optic discs is enlarged. These facts point to the contribution of an abnormal developmental mechanism in the ataxia of Charlevoix-Saguenay. Accordingly, spasticity would be mediated by compression of the pyramidal tracts, neuromuscular symptoms by secondary axonal degeneration superimposed on the peripheral myelinopathy, while the cause of the progressive ataxia remains speculative. The distinctive aspect of the dorsal spine could be of help in the clinical diagnosis.     

Evaluating the Feasibility of a Play-Based Telehealth Intervention Program for Children with Prader–Willi Syndrome

Here we report the feasibility and acceptability of telehealth for direct intervention in children with Prader–Willi syndrome (PWS). Children with PWS have social-cognitive challenges that are similar to children with ASD. However, developing behavioral interventions for individuals with PWS is faced with the significant challenge of enrolling enough participants for local studies where multiple visits per week are indicated for effective intervention. This study delivered a 6-week play-based intervention via telehealth directly to eight children with PWS (6–12 years). Participants completed the program with minimal behavioral or technological difficulty (#sessions M?=?11.875/12). Behavioral Intervention Rating Scale results indicate good acceptability (M?=?5.54/6.00). These findings support using telehealth in rare disorders and delivering intervention directly to children with developmental delays through this modality.     

Mutation Screening of the γ-Aminobutyric Acid Type-A Receptor Subunit γ2 Gene in Korean Patients with Childhood Absence Epilepsy

Background and Purpose

Since the γ-aminobutyric acid type-A receptor subunit γ2 gene (GABRG2) mutation was discovered in an Australian family with childhood absence epilepsy (CAE) and febrile convulsions, a few screening studies for the GABRG2 mutation have been conducted in sporadic individuals with CAE from other ethnic groups. The aim of this study was to determine whether or not the previously reported genetic mutations and single-nucleotide polymorphisms (SNPs) of GABRG2 can be reproduced in sporadic Korean individuals with CAE, compared to healthy Korean individuals.

Methods

Thirty-five children with CAE in Chonnam National University Hospital and healthy controls (n=207) were enrolled, and the medical records of patients with CAE were reviewed. CAE was diagnosed according to the Classification and Terminology of the International League Against Epilepsy. All nine exons of GABRG2 were directly sequenced. In addition, the two SNPs found in our CAE patients were analyzed: C315T in exon 3 (E3) and C588T in exon 5 (E5). The frequencies of the two SNPs in the CAE patients were compared with data from healthy controls (for E3 and E5) and from previously reported Korean population data (only for E3).

Results

No mutation of GABRG2 was found in our CAE patients. In addition, the allele and genotype frequencies of the two polymorphisms did not differ significantly between CAE patients, healthy controls, and the Korean general population (p>0.05).

Conclusions

Our study of sporadic Korean individuals with CAE found no evidence that GABRG2 contributes to the genetic basis of CAE.     

Factors in Maintaining a Stable Patient–Physician Relationship among Individuals with Schizophrenia

This study aimed to determine whether adequate continuity of care (COC) existed among individuals with schizophrenia, and what the associated determinants were. The National Health Insurance Research Database of Taiwan was used to identify individuals with newly diagnosed schizophrenia from 2000 to 2009. Two outcome indicators were first derived to conduct the continuity assessment based on the usual provider continuity (UPC) index and the continuity of care index (COCI). The average scores of the UPC and COCI were 0.78 and 0.67, respectively. Patients who have been hospitalized, with lower income, and unemployed had significantly poorer continuity of care. In addition, patients were cared for by higher caseload physicians, treated at mental health specialty institutions, and at hospital outpatient settings also experienced significantly poorer continuity. Patients cared for by middle-aged physicians, psychiatrists, and treated at private institutions had significantly better continuity of mental health care.     

Use of perampanel in children and adolescents with Lennox–Gastaut Syndrome

AimReport the use of perampanel treatment in children with Lennox–Gastaut syndrome (LGS).MethodWe conducted a prospective study of 13 LGS patients (seven male; mean age, 12.8 years) treated with adjunctive perampanel therapy. Perampanel was initiated at 2 mg/day and titrated to a median maximum dose of 6 mg/day.ResultsAfter a mean follow-up duration of 10.8 months (range, 1–24 months), nine patients (69.2%) were responders (≥ 50% reduction in total seizure frequency) and nine (69.2%) were rated by their physician as “much improved” or “very much improved”. Four patients (30.8%) discontinued perampanel due to the lack of efficacy (n = 2) and seizure aggravation (n = 2). No patients discontinued due to other adverse events (AEs). AEs were reported for six patients (46.2%) and comprised decreased activity/social interaction (n = 3), behavior disturbance with agitation (n = 2), and/or fatigue (n = 2). All AEs became manageable after perampanel dosing was decreased. Improvements in cognitive function and/or behavior were reported for seven patients (53.8%). Introduction of perampanel allowed the dose reduction and/or discontinuation of other treatments in seven patients (53.8%).InterpretationPerampanel was efficacious and generally well tolerated as an adjunctive treatment for seizures associated with LGS, supporting further research in this area.