Congenital Myasthenic Syndromes with COLQ mutations: Long term follow-up

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagenlike tail subunit gene (ColQ) cause recessive forms of synaptic CMS with end plate AChE deficiency. We report the time course of clinical manifestations in 15 COLQ-mutated patients followed from 1987 to 2010. All patients suffered from a muscle weakness with onset at birth or in childhood. Ocular and bulbar signs were found in 60% of the patients and delayed pupillary light response in 20% of our patients. EMG study demonstrated a decrement on repetitive nerve stimulation and repetitive compound muscle action potential in all patients. Clinical symptoms strongly fluctuated daily, weekly, monthly or even yearly. Severe relapses were characterized by a general motor weakness associated with pain which resolved spontaneously after a few months whereas the relapses with these symptoms and bulbar signs could last up to several years. Genetic analyses identified 16 different mutations including 9 novel ones. There was no genotype-phenotype correlation. Our study confirms the predominance of oculobulbar signs and the frequency of respiratory distress in COLQrelated CMS. At the end of the follow up of 23 years, interesting findings were (i) the spontaneous reversibility of severe relapses, some of them lasting for up to 5 years (ii) the good prognosis of COLQ-related CMS, since at the end of the follow-up 80% of patients were ambulant and 87% of patients had no respiratory trouble (iii) the efficacy of Ephedrine and, to a lesser extend, of 3-4 DAP. The triggering factors of relapses were esterase inhibitors, effort, puberty, pregnancy and delivery highlighting the importance of hormonal factors in CMS. In conclusion, patients diagnosed with unknown congenital myopathy should undergo an electrophysiological study of neuromuscular junction to identify ColQ-related CMS.

Disorders of pupillary structure and function.

Neurologists are frequently consulted because of a pupillary abnormality. An unequal size of the pupils, an unusual shape, white colored pupils, or a poorly reactive pupil are common reasons for referral. A directed history and careful observation of the iris and pupil movements can bear out ocular pathology such as congenital or structural anomalies as the cause of abnormal pupils. Thereafter, it is important to evaluate the neurologic causes of anisocoria and poor pupil function. The first part of this article emphasizes pupillary abnormalities frequently encountered in infants and children and discusses some of the more common acquired iris structural defects. The second part focuses on evaluation of lesions in the neural pathways that result in pupillary dysfunction, with particular attention to those conditions having neurologic, systemic, or visual implications.

Reversible acquired epileptic frontal syndrome and CSWS suppression in a child with congenital hemiparesis treated by hemispherotomy.

A boy with a right congenital hemiparesis due to a left pre-natal middle cerebral artery infarct developed focal epilepsy at 33 months and then an insidious and subsequently more rapid, massive cognitive and behavioural regression with a frontal syndrome between the ages of 4 and 5 years with continuous spike-waves during sleep (CSWS) on the EEG. Both the epilepsy and the CSWS were immediately suppressed by hemispherotomy at the age of 5 years and 4 months. A behavioural-cognitive follow-up prior to hemispherotomy, an per-operative EEG and corticography and serial post-operative neuropsychological assessments were performed until the age of 11 years. The spread of the epileptic activity to the "healthy" frontal region was the cause of the reversible frontal syndrome. A later gradual long-term but incomplete cognitive recovery, with moderate mental disability was documented. This outcome is probably explained by another facet of the epilepsy, namely the structural effects of prolonged epileptic discharges in rapidly developing cerebral networks which are, at the same time undergoing the reorganization imposed by a unilateral early hemispheric lesion. Group studies on the outcome of children before and after hemispherectomy using only single IQ measures, pre- and post-operatively, may miss particular epileptic cognitive dysfunctions as they are likely to be different from case to case. Such detailed and rarely available complementary clinical and EEG data obtained in a single case at different time periods in relation to the epilepsy, including per-operative electrophysiological findings, may help to understand the different cognitive deficits and recovery profiles and the limits of full cognitive recovery.

Absence of the fourth cranial nerve in congenital Brown syndrome.

PURPOSE: To elucidate the aetiology of congenital Brown syndrome. METHODS: Four consecutive patients diagnosed with unilateral congenital Brown syndrome had a comprehensive standardized ocular motility examination. Any compensatory head posture was measured. Brain magnetic resonance imaging (MRI) with regard for the IV cranial nerve (CN) was performed in all patients. Orbital MRI was performed in 2/4 patients, with images acquired in eight directions of gaze and superior oblique (SO) muscle areas compared. RESULTS: CN IV could not be identified bilaterally in two patients, but was absent only on the side of the Brown syndrome in the two other patients. On the normal side, orbital MRI revealed a smaller SO muscle area in upgaze than in downgaze, demonstrating normal actions of this muscle. On the side of the Brown syndrome, the SO area remained the same in upgaze and in downgaze and approximately symmetric to the area of SO in downgaze on the normal side. CONCLUSIONS: These cases add further anatomical support to the theory of paradoxical innervation in congenital Brown syndrome. CN IV was absent in two patients on the side of the Brown syndrome, but without muscle hypoplasia. SO muscle size did not vary in up- and downgaze, which we interpreted as a sign of constant innervation through branches of CN III.

Regional cortical volumes and congenital heart disease: a MRI study in 22q11.2 deletion syndrome.

Children with congenital heart disease (CHD) who survive surgery often present impaired neurodevelopment and qualitative brain anomalies. However, the impact of CHD on total or regional brain volumes only received little attention. We address this question in a sample of patients with 22q11.2 deletion syndrome (22q11DS), a neurogenetic condition frequently associated with CHD. Sixty-one children, adolescents, and young adults with confirmed 22q11.2 deletion were included, as well as 80 healthy participants matched for age and gender. Subsequent subdivision of the patients group according to CHD yielded a subgroup of 27 patients with normal cardiac status and a subgroup of 26 patients who underwent cardiac surgery during their first years of life (eight patients with unclear status were excluded). Regional cortical volumes were extracted using an automated method and the association between regional cortical volumes, and CHD was examined within a three-condition fixed factor. Robust protection against type I error used Bonferroni correction. Smaller total cerebral volumes were observed in patients with CHD compared to both patients without CHD and controls. The pattern of bilateral regional reductions associated with CHD encompassed the superior parietal region, the precuneus, the fusiform gyrus, and the anterior cingulate cortex. Within patients, a significant reduction in the left parahippocampal, the right middle temporal, and the left superior frontal gyri was associated with CHD. The present results of global and regional volumetric reductions suggest a role for disturbed hemodynamic in the pathophysiology of brain alterations in patients with neurodevelopmental disease and cardiac malformations.

Anorectal malformations and pregnancy-related disorders: a registry-based case-control study in 17 European regions.

OBJECTIVE: To identify pregnancy-related risk factors for different manifestations of congenital anorectal malformations (ARMs). DESIGN: A population-based case-control study. SETTING: Seventeen EUROCAT (European Surveillance of Congenital Anomalies) registries, 1980-2008. POPULATION: The study population consisted of 1417 cases with ARM, including 648 cases of isolated ARM, 601 cases of ARM with additional congenital anomalies, and 168 cases of ARM-VACTERL (vertebral, anal, cardiac, tracheo-esophageal, renal, and limb defects), along with 13 371 controls with recognised syndromes or chromosomal abnormalities. METHODS: Multiple logistic regression analyses were used to calculate adjusted odds ratios (ORs) for potential risk factors for ARM, such as fertility treatment, multiple pregnancy, primiparity, maternal illnesses during pregnancy, and pregnancy-related complications. MAIN OUTCOME MEASURES: Adjusted ORs for pregnancy-related risk factors for ARM. RESULTS: The ARM cases were more likely to be firstborn than the controls (OR 1.6, 95% CI 1.4-1.8). Fertility treatment and being one of twins or triplets seemed to increase the risk of ARM in cases with additional congenital anomalies or VACTERL (ORs ranging from 1.6 to 2.5). Maternal fever during pregnancy and pre-eclampsia were only associated with ARM when additional congenital anomalies were present (OR 3.9, 95% CI 1.3-11.6; OR 3.4, 95% CI 1.6-7.1, respectively), whereas maternal epilepsy during pregnancy resulted in a five-fold elevated risk of all manifestations of ARM (OR 5.1, 95% CI 1.7-15.6). CONCLUSIONS: This large European study identified maternal epilepsy, fertility treatment, multiple pregnancy, primiparity, pre-eclampsia, and maternal fever during pregnancy as potential risk factors primarily for complex manifestations of ARM with additional congenital anomalies and VACTERL.

Identification of heart rate-associated loci and their effects on cardiac conduction and rhythm disorders.

Elevated resting heart rate is associated with greater risk of cardiovascular disease and mortality. In a 2-stage meta-analysis of genome-wide association studies in up to 181,171 individuals, we identified 14 new loci associated with heart rate and confirmed associations with all 7 previously established loci. Experimental downregulation of gene expression in Drosophila melanogaster and Danio rerio identified 20 genes at 11 loci that are relevant for heart rate regulation and highlight a role for genes involved in signal transmission, embryonic cardiac development and the pathophysiology of dilated cardiomyopathy, congenital heart failure and/or sudden cardiac death. In addition, genetic susceptibility to increased heart rate is associated with altered cardiac conduction and reduced risk of sick sinus syndrome, and both heart rate-increasing and heart rate-decreasing variants associate with risk of atrial fibrillation. Our findings provide fresh insights into the mechanisms regulating heart rate and identify new therapeutic targets.

Neuronal calcium channel mutation in a patient with congenital ataxia and attacks of hemiplegic migraine with cerebral edema

Background: Familial Hemiplegic Migraine (FHM), characterized by a prolonged unilateral hemiparesis, mainly results from mutations in the alpha-1a subunit of the calcium channel gene CACNA1A that can also cause two other dominantly inherited neurological disorders, Episodic Ataxia type 2 (EA2, with sometimes migrainous headaches) and Spinocerebellar Ataxia type 6 (SCA6, late-onset and progressive). A same mutation can have different clinical expression in a family (hemiplegic migraine, migraine-coma, cerebellar ataxia). CACNA1A mutations in FHM are usually missense, leading to gain-of-function, while truncating mutations leading to loss-of-function are usually associated with EA2. Case report: This 9-year-old girl was seen as a baby for hypotonia and transient vertical nystagmus. Her first brain MRI was normal. She evolved as a congenital ataxia, but since the age of two, she had attacks of coma, hemiparesis (either side), partial seizures, dystonic movements and fever. Attacks were initially triggered by minor head bumps, subsequently spontaneous. Brain MRIs in the acute stage always showed transient unilateral hemisphere swelling. Follow-up images revealed atrophic lesions in the temporo-occipital regions and cerebellar atrophy. A prophylactic trial with flunarizine was ineffective. Acetazolamide was recently introduced. Methods: Since our patient shared features of both FHM and EA2, we studied the CACNA1A gene by direct sequencing in the patient's and parents' DNA. Results: We identified an unreported de novo heterozygous deletion of three base pairs (c.4503_4505delCTT) predicting the deletion of one amino acid (p.Phe1502del). The CACNA1A protein contains 4 domains, each formed by six transmembrane segments. The deletion is located in a highly conserved region in segment 6 (S6) of the third domain. Mutations in S6 segments of calcium channels change single-channel conductance and channel selectivity, most resulting in loss-of-function. Outlook: In vitro expression studies of the identified mutation are underway, aiming at understanding its functional consequences and finding an efficient treatment.

The role of epilepsy in early language development in a child with a congenital lesion in the right hemisphere

Early epilepsy is known to worsen the developmental prognosis of young children with a congenital focal brain lesion, but its direct role is often very difficult to delineate from the other variables. This requires prolonged periods of follow-up with simultaneous serial electrophysiological and developmental assessments which are rarely obtained. We studied a male infant with a right prenatal infarct in the territory of the right middle cerebral artery resulting in a left spastic hemiparesis, and an epileptic disorder (infantile spasms with transient right hemihypsarrhythmia and focal seizures) from the age of 7 months until the age of 4 years. Pregnancy and delivery were normal. A dissociated delay of early language acquisition affecting mainly comprehension without any autistic features was documented. This delay was much more severe than usually expected in children with early focal lesions, and its evolution, with catch-up to normal, was correlated with the active phase of the epilepsy. We postulate that the epilepsy specifically amplified a pattern of delayed language emergence, mainly affecting lexical comprehension, reported in children with early right hemisphere damage.

Analyse critique des résultats de biopsies musculaires et de la méthodologie utilisée dans 889 cas d'affections neuromusculaires [Critical analysis of the results of muscle biopsies and of the methods used in 889 cases of neuromuscular disorders]

The contribution of muscle biopsies to the diagnosis of neuromuscular disorders and the indications of various methods of examination are investigated by analysis of 889 biopsies from patients suffering from myopathic and/or neurogenic disorders. Histo-enzymatic studies performed on frozen material as well as immunohistochemistry and electron microscopy allowed to provide specific diagnoses in all the neurogenic disorders (polyneuropathies and motor neuron diseases), whereas one third of myopathies remained uncertain. Confrontation of neuropathological data with the clinical indications for histological investigations shows that muscle biopsies reveal the diagnosis in 25% of the cases (mainly in congenital and metabolic myopathies) and confirm and/or complete the clinical diagnosis in 50%. In the remaining cases with non specific abnormalities neuropathological investigations may help the clinician by excluding well defined neuromuscular disorders. Analysis of performed studies and results of investigations show the contribution and specificity of each method for the diagnosis. Statistical evaluation of this series indicates that cryostat sectioning for histo- and immunochemical and electron microscopy increases the rate of diagnoses of neuromuscular diseases: full investigation was necessary for the diagnosis in 30% of the cases. The interpretation of the wide range of pathological reactions in muscles requires a close cooperation with the clinician.

Pédiatrie. 3. Traitement du membre supérieur dans les hémiparésies congénitales: progrès et perspectives [Pediatrics. Upper limb treatment in congenital hemiparesis: progress and perspectives].

Congenital hemiparesis is one of the most frequent pediatric motor disorders. Upper limb rehabilitation of the hemiparetic child has considerably evolved during the last decade by the use of focal chemical denervation (intramuscular botulinum toxin) and the introduction of novel rehabilitation techniques such as constraint induced movement therapy or robotic reeducation.

Long-term follow-up of patients with congenital myasthenic syndrome caused by COLQ mutations.

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous inherited disorders characterized by impaired neuromuscular transmission. Mutations in the acetylcholinesterase (AChE) collagen-like tail subunit gene (COlQ) cause recessive forms of synaptic CMS with end plate AChE deficiency. We present data on 15 COLQ -mutant CMS carrying 16 different mutations (9 novel ones identified) followed-up for an average period of 10 ears. The mean age at the first examination was 19 ears old (range from 3 to 48). We report relapses during short or long-term periods characterized by worsening of muscle weakness sometimes associated with respiratory crises. All the relapses ended spontaneously or with 3-4 DAP or ephedrine with no residual impairment. The triggering factors identified were esterase inhibitors, effort, puberty or pregnancy highlighting the importance of hormonal factors. There was no genotype-phenotype correlation. At the end of the follow-up, 80% of patients were ambulant and 87% of patients had no respiratory trouble in spite of severe relapses.

Leri's pleonosteosis, a congenital rheumatic disease, results from microduplication at 8q22.1 encompassing GDF6 and SDC2 and provides insight into systemic sclerosis pathogenesis.

OBJECTIVES: Leri's pleonosteosis (LP) is an autosomal dominant rheumatic condition characterised by flexion contractures of the interphalangeal joints, limited motion of multiple joints, and short broad metacarpals, metatarsals and phalanges. Scleroderma-like skin thickening can be seen in some individuals with LP. We undertook a study to characterise the phenotype of LP and identify its genetic basis. METHODS AND RESULTS: Whole-genome single-nucleotide polymorphism genotyping in two families with LP defined microduplications of chromosome 8q22.1 as the cause of this condition. Expression analysis of dermal fibroblasts from affected individuals showed overexpression of two genes, GDF6 and SDC2, within the duplicated region, leading to dysregulation of genes that encode proteins of the extracellular matrix and downstream players in the transforming growth factor (TGF)-β pathway. Western blot analysis revealed markedly decreased inhibitory SMAD6 levels in patients with LP. Furthermore, in a cohort of 330 systemic sclerosis cases, we show that the minor allele of a missense SDC2 variant, p.Ser71Thr, could confer protection against disease (p<1×10(-5)). CONCLUSIONS: Our work identifies the genetic cause of LP in these two families, demonstrates the phenotypic range of the condition, implicates dysregulation of extracellular matrix homoeostasis genes in its pathogenesis, and highlights the link between TGF-β/SMAD signalling, growth/differentiation factor 6 and syndecan-2. We propose that LP is an additional member of the growing 'TGF-β-pathies' group of musculoskeletal disorders, which includes Myhre syndrome, acromicric dysplasia, geleophysic dysplasias, Weill-Marchesani syndromes and stiff skin syndrome. Identification of a systemic sclerosis-protective SDC2 variant lays the foundation for exploration of the role of syndecan-2 in systemic sclerosis in the future.

Evaluation of common mental disorders in women with polycystic ovary syndrome and its relationship with body mass index

PURPOSE: To evaluate the prevalence of common mental disorders in women diagnosed with polycystic ovary syndrome as compared with paired controls without this syndrome. METHODS: Cross-sectional study with a Control Group examining women between the ages of 18 and 30 who did not use antidepressants and who sought the Gynecology Service of the researched sites. For every woman diagnosed with the polycystic ovary syndrome, another with the same age, educational status and presence or absence of sexual partners was sought without this diagnosis. In total, 166 patients agreed to participate, consisting of 95 diagnosed with polycystic ovary syndrome and 71 in the Control Group. The diagnosis of polycystic ovary syndrome was made by the presence of two from three criteria: oligomenorrhea or amenorrhea, clinical or biochemical hyperandrogenism and polycystic ovaries on transvaginal ultrasound, following exclusion of patients with Cushing's syndrome, congenital adrenal hyperplasia, and androgen-secreting tumors. Weight and height were measured to calculate the body mass index. The Self-Reporting Questionnaire, which evaluated 20 items, was used as an indicator of common mental disorders. A χ² analysis stratified by the category of body mass index was used to compare the prevalence of common mental disorders, between the groups of women with and without the polycystic ovary syndrome. RESULTS: There were no significant differences in age, education, presence of sexual partners, ethnicity, socioeconomic status, use of psychiatric medication, and search for consultation in mental health between the studied groups. The prevalence of obese women with indications of common mental disorders was significantly higher in women with polycystic ovary syndrome than in the Control Group. In the group with healthy body mass index, the incidence of common mental disorders was statistically significant different between women with polycystic ovary syndrome and normal controls (p=0.008). CONCLUSIONS: Women with diagnosis of this disease have an almost three-fold increased likelihood of common mental disorders as compared with those without polycystic ovary syndrome. Although obesity is often observed in polycystic ovary syndrome, even women with a healthy body mass index have an increased risk of psychiatric comorbidity.