Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Virtual Rehabilitation through Nintendo Wii in Poststroke Patients: Follow-Up.

OBJECTIVE: To evaluate in the follow-up the sensory-motor recovery and quality of life patients 2 months after completion of the Nintendo Wii console intervention and determine whether learning retention was obtained through the technique. METHODS: Five hemiplegics patients participated in the study, of whom 3 were male with an average age of 54.8 years (SD = 4.6). Everyone practiced Nintendo Wii therapy for 2 months (50 minutes/day, 2 times/week, during 16 sessions). Each session lasting 60 minutes, under a protocol in which only the games played were changed, plus 10 minutes of stretching. In the first session, tennis and hula hoop games were used; in the second session, football (soccer) and boxing were used. For the evaluation, the Fulg-Meyer and Short Form Health Survey 36 (SF-36) scales were utilized. The patients were immediately evaluated upon the conclusion of the intervention and 2 months after the second evaluation (follow-up). RESULTS: Values for the upper limb motor function sub-items and total score in the Fugl-Meyer scale evaluation and functional capacity in the SF-36 questionnaire were sustained, indicating a possible maintenance of the therapeutic effects. CONCLUSION: The results suggest that after Nintendo Wii therapy, patients had motor learning retention, achieving a sustained benefit through the technique.

An unusual cause of blindness: infarction in the bilateral lateral geniculate bodies.

A 10-year-old girl presented with acute blindness after a severe episode of febrile diarrhea. Magnetic resonance images were consistent with the diagnosis of infarction in the bilateral lateral geniculate bodies.

Social anxiety score is high in adolescents with chronic migraine.

BACKGROUND: Social anxiety disorder, also known as social phobia, is a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. It usually begins in mid-adolescence and has a chronic course and interferes in academic, social, family and personal functioning. Recent studies have shown that social anxiety disorder is more prevalent in adults with migraine. Little evidence on this subject is available for the adolescent population. METHODS: This study was performed between August 2009 and August 2010; all patients were recruited in schools, pediatric or neuropediatric facilities, and were submitted to a detailed headache questionnaire, which consisted of demographic and clinical data. To evaluate social anxiety, the Social Phobia Inventory was used. RESULTS: A total of 151 subjects were evaluated: 50 had chronic migraine, 50 had episodic migraine and 51 were control subjects. In the chronic migraine group, the mean score in the Social Phobia Inventory was 18.5 ± 12.4, which was significantly higher than in the episodic migraine group (12.1 ± 8.1) and in the control group (13.8 ± 10.8; F(2131) = 4.8, P= 0.010). The mean score, however, was not significantly different between the control and episodic migraine groups. CONCLUSIONS: Chronic migraine is strongly associated with high social anxiety score, regardless of demographic data and pain intensity. The total burden of migraine may be increased with social anxiety disorder comorbidity.

Hemifacial spasm as a manifestation of pilocytic astrocytoma in a pediatric patient.

Hemifacial spasm is a disorder of the seventh cranial nerve, which is characterized by irregular, involuntary and recurrent tonic and clonic contractions of the ipsilateral facial expression muscles. This disorder affects mainly adults, and there are few cases reported in childhood. The main etiologies are vascular problems, although tumors are an important cause of hemifacial spasm via a direct or an indirect mass effect. We report a 6-year-old girl who presented with right hemifacial spasm. Magnetic resonance imaging showed a lesion in the cerebellopontine angle, extending from the midbrain to the pons with a slight mass effect on the fourth ventricle. The histological examination revealed a pilocytic astrocytoma.

Sensitivity to aversive stimulation, posttraumatic symptoms and migraines: what do they have in common?

Studies have suggested that the high comorbidity observed between chronic migraine and anxiety disorders can be mediated through a third factor namely increased sensitivity to aversive stimulation. This trait may predispose for both chronic migraines, through medication overuse as an avoidance response, and anxiety disorders. Additional studies have shown that hyper sensitivity to aversive stimulation, migraine chronification and anxiety disorders share other characteristics such as serotonergic mediation and personality traits. Preliminary analysis of empirical data comparing the frequency the impact of traumatic events over chronic [CM] and episodic migraine [EM] patients gives further support to this hypothesis. In spite of CM and EM did not differ in terms of the occurrence of traumatic events, CM patients that had experienced at least one traumatic event during their lives had higher scores in re-experiencing and avoidance (but not in hyperarousal) symptoms than CM patients. These observations suggest that traumatic events have greater impact over CM than over EM patients.

Urinary 6-sulphatoxymelatonin levels are depressed in chronic migraine and several comorbidities.

OBJECTIVE: To assess urinary 6-sulphatoxymelatonin levels in a large consecutive series of patients with migraine and several comorbidities (chronic fatigue, fibromyalgia, insomnia, anxiety, and depression) as compared with controls. BACKGROUND: Urine analysis is widely used as a measure of melatonin secretion, as it is correlated with the nocturnal profile of plasma melatonin secretion. Melatonin has critical functions in human physiology and substantial evidence points to its importance in the regulation of circadian rhythms, sleep, and headache disorders. METHODS: Urine samples were collected into a single plastic container over a 12-hour period from 8:00 pm to 8:00 am of the next day, and 6-sulphatoxymelatonin was measured by quantitative ELISA. All of the patients were given a detailed questionnaire about headaches and additionally answered the following questionnaires: Chalder fatigue questionnaire, Epworth somnolence questionnaire, State-Trait Anxiety Inventory, and the Beck Depression Inventory. RESULTS: A total of 220 subjects were evaluated - 73 (33%) had episodic migraine, 73 (33%) had chronic migraine, and 74 (34%) were enrolled as control subjects. There was a strong correlation between the concentration of 6-sulphatoxymelatonin detected and chronic migraine. Regarding the comorbidities, this study objectively demonstrates an inverse relationship between 6-sulphatoxymelatonin levels and depression, anxiety, and fatigue. CONCLUSIONS: To our knowledge, this is the first study to evaluate the relationship between the urinary concentration of melatonin and migraine comorbidities. These results support hypothalamic involvement in migraine pathophysiology.

Phobias, other psychiatric comorbidities and chronic migraine / Fobias, outras comorbidades psiquiátricas e enxaqueca crônica

BACKGROUND: Comorbidity of chronic migraine (CM) with psychiatric disorders, mostly anxiety and mood disorders, is a well-recognized phenomenon. Phobias are one of the most common anxiety disorders in the general population. Phobias are more common in migraineurs than non-migraineurs. The clinical profile of phobias in CM has never been studied. METHOD: We investigated the psychiatric profile in 56 patients with CM using the SCID I/P interview. RESULTS: Lifetime criteria for at least one mental disorder was found in 87.5 percent of the sample; 75 percent met criteria for at least one lifetime anxiety disorder and 60.7 percent of our sample fulfilled DSM-IV criteria for lifetime phobic avoidant disorders. Mood and anxiety scores were higher in phobic patients than in non-phobic CM controls. Number of phobias correlated with higher levels of anxiety and depression. CONCLUSION: Phobias are common in CM. Its recognition may influence its management. Early treatment may lead to better prognosis.

INTRODUÇÃO: As comorbidades psiquiátricas das enxaquecas crônicas são bem conhecidas. As fobias, transtorno ansioso mais comum, são mais prevalentes entre enxaquecosos do que entre não enxaquecosos. O perfil clínico de fobias em uma população enxaquecosa nunca foi estudado. MÉTODO: Estudamos aspectos psiquiátricos de uma população de 56 pacientes com enxaqueca crônica. RESULTADOS: Usando o SCID I/P para o DSM-IV, critérios diagnósticos para ao menos algum transtorno psiquiátrico durante a vida foram preenchidos por 87,5 por cento de nossa amostra, 75 por cento para ao menos um transtorno ansioso e 60,7 por cento para condições fóbicas em algum momento de suas vidas. Os escores de ansiedade e humor foram maiores entre os fóbicos e o número de fobias teve correlação positiva com o grau de ansiedade e depressão. CONCLUSÃO: Fobias são comuns na enxaqueca crônica e seu reconhecimento poderia influenciar seu manejo e melhorar seu prognóstico.

Potential therapeutic use of melatonin in migraine and other headache disorders.

There is increasing evidence that headache disorders are connected with melatonin secretion and pineal function. Some headaches have a clearcut seasonal and circadian pattern, such as cluster and hypnic headaches. Melatonin levels have been found to be decreased in both migraine and cluster headaches. Melatonin mechanisms are related to headache pathophysiology in many ways, including its anti-inflammatory effect, toxic free radical scavenging, reduction of pro-inflammatory cytokine upregulation, nitric oxide synthase activity and dopamine release inhibition, membrane stabilisation, GABA and opioid analgesia potentitation, glutamate neurotoxicity protection, neurovascular regulation, 5-HT modulation and the similarity in chemical structure to indometacin. The treatment of headache disorders with melatonin and other chronobiotic agents, such as melatonin agonists (ramelteon and agomelatin), is promising and there is a great potential for their use in headache treatment.

Mutation in filamin A causes periventricular heterotopia, developmental regression, and West syndrome in males.

PURPOSE: Familial periventricular heterotopia (PH) represents a disorder of neuronal migration resulting in multiple gray-matter nodules along the lateral ventricular walls. Prior studies have shown that mutations in the filamin A (FLNA) gene can cause PH through an X-linked dominant pattern. Heterozygotic female patients usually remain asymptomatic until the second or third decade of life, when they may have predominantly focal seizures, whereas hemizygotic male fetuses typically die in utero. Recent studies have also reported mutations in FLNA in male patients with PH who are cognitively normal. We describe PH in three male siblings with PH due to FLNA, severe developmental regression, and West syndrome. METHODS: The study includes the three affected brothers and their parents. Video-EEG recordings and magnetic resonance image (MRI) scanning were performed on all individuals. Mutations for FLNA were detected by using polymerase chain reaction (PCR) on genomic DNA followed by single-stranded conformational polymorphism (SSCP) analysis or sequencing. RESULTS: Two of the siblings are monozygotic twins, and all had West syndrome with hypsarrhythmia on EEG. MRI of the brain revealed periventricular nodules of cerebral gray-matter intensity, typical for PH. Mutational analyses demonstrated a cytosine-to-thymidine missense mutation (c. C1286T), resulting in a threonine-to-methionine amino acid substitution in exon 9 of the FLNA gene. CONCLUSIONS: The association between PH and West syndrome, to our knowledge, has not been previously reported. Males with PH have been known to harbor FLNA mutations, although uniformly, they either show early lethality or survive and have a normal intellect. The current studies show that FLNA mutations can cause periventricular heterotopia, developmental regression, and West syndrome in male patients, suggesting that this type of FLNA mutation may contribute to severe neurologic deficits.

Phobias, other psychiatric comorbidities and chronic migraine.

BACKGROUND: Comorbidity of chronic migraine (CM) with psychiatric disorders, mostly anxiety and mood disorders, is a well-recognized phenomenon. Phobias are one of the most common anxiety disorders in the general population. Phobias are more common in migraineurs than non-migraineurs. The clinical profile of phobias in CM has never been studied. METHOD: We investigated the psychiatric profile in 56 patients with CM using the SCID I/P interview. RESULTS: Lifetime criteria for at least one mental disorder was found in 87.5% of the sample; 75% met criteria for at least one lifetime anxiety disorder and 60.7% of our sample fulfilled DSM-IV criteria for lifetime phobic avoidant disorders. Mood and anxiety scores were higher in phobic patients than in non-phobic CM controls. Number of phobias correlated with higher levels of anxiety and depression. CONCLUSION: Phobias are common in CM. Its recognition may influence its management. Early treatment may lead to better prognosis.