Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome: A novel mutation and in silico analyses

Brown-Vialetto-Van Laere syndrome, a rare neurological disorder is due to SLC52A3 mutations. Here, the SLC52A3 protein and its mutations are in silico structurally and functionally analyzed among all the reported patients and a novel mutation is also reported.After clinical evaluations, SLC52A3 gene was sequenced and segregation analysis of the mutations was also checked. A comprehensive search was performed on the reported mutations of SLC52A3 gene. In silico structural and functional analyses of the mutations and interactome analyses of the protein were done using available software tools.Mutations of 37 affected individuals were identified. Thirty three mutations were determined. c.502A > C was a novel variant that it was segregated within the family. One mutation (c.639C > G) was responsible for 12% of the mutations. Segregation analysis, secondary structure, functional prediction achieved for the novel mutation showed pathogenicity of this variant.BVVL is a very rare disorder; SLC52A3 mutations are distributed among different populations and there might be one frequent mutation in this gene. BVVL should be more considered in Iran. In addition to segregation analysis, computational analyses could accelerate understanding the extent of pathogenicity of the novel variants.     

Adrenomyeloneuropathy with bulbar palsy: A rare association

Adrenomyeloneuropathy (AMN) is a variant of adrenoleukodystrophy (ALD), an X-linked recessive peroxisomal disorder associated with accumulation of very long chain fatty acids (VLCFA). Mutations of this gene lead to abnormal peroxisomal β-oxidation, which results in the harmful accumulation of VLCFAs in affected cells. Neurological symptoms occur due to progressive demyelination and destruction of cerebral white matter and primary adrenal insufficiency. Bulbar palsy in a case of AMN is very unusual. We report a case of a 22-year-old male with AMN who developed adrenal insufficiency at the age of 4 years successfully treated by gluco- and mineralocorticoids followed by features of myeloneuropathy with bulbar palsy. AMN with prominent bulbar symptoms emphasizes the diverse clinical manifestation of this disease.     

The experience of siblings of individuals with CHARGE syndrome

Background We investigated the experience of siblings of children with CHARGE syndrome (n?=?29). Siblings of children with a disability are an understudied population, and, to our knowledge, this is the first investigation of the sibling relationship in CHARGE.

Method Participants were asked to complete 5 measures: (a) Sibling Evaluation Questionnaire, (b) UCLA Loneliness Scale, (c) Network Orientation Scale, (d) Family Hardiness Index, and (e) Family Member Well-Being Index.

Results Participants accepted their sibling with CHARGE, with the relationship being neither highly negative nor positive. Although siblings reported to be somewhat less lonely, they were no less likely to access social support than college-aged peers. Participants did not indicate adjustment issues; however, more than half of the siblings reported avoiding adding to their parents’ stress. Further, they rated their own personal wellbeing very positively.

Conclusion In spite of acknowledging stress within the family, these siblings represent themselves as well adjusted with a somewhat typical sibling relationship.     

Novel IARS2 mutations in Japanese siblings with CAGSSS,Leigh, and West syndrome

Background

IARS2 encodes isoleucine-tRNA synthetase, which is aclass-1 amino acyl-tRNA synthetase. IARS2 mutations are reported to cause Leigh syndrome or cataracts, growth hormone deficiency, sensory neuropathy, sensorineural hearing loss, and skeletal dysphasia syndrome (CAGSSS). To our knowledge, IARS2 mutations and diseases related to it have only been reported in three families. Here we report a case of two Japanese siblings with Leigh syndrome, some features of CAGSSS, and West syndrome that are found to have compound heterozygous novel IARS2 mutations.

Refining clinical phenotypes by contrasting ethnically different populations with schizophrenia from Australia, India and Sarawak

We contrasted demographic and clinical characteristics in transethnic schizophrenia populations from Australia (n=821), India (n=520) and Sarawak, Malaysia (n=298) and proposed cultural explanations for identified site differences. From these we aimed to identify candidate variables free from significant cultural confounding that are hence suitable for inclusion in genetic analyses. We observed five phenomena: (1) more individuals were living alone in Australia than India or Sarawak; (2) drug use was lower in India than Australia or Sarawak; (3) duration of untreated psychosis (DUP) was longer in India than Australia or Sarawak; (4) the rate of schizoaffective disorder was lower in India than Australia or Sarawak; and (5) age at psychosis onset (AAO) was older in Sarawak than Australia or India. We suggest that site differences for living arrangements, drug use and DUP are culturally confounded. The schizoaffective site difference likely results from measurement bias. The AAO site difference, however, has no obvious cultural or measurement bias explanation. Therefore, this may be an ideal candidate for use in genetic studies, given that genetic variants affecting AAO have already been proposed.     

Adult siblings of individuals with Down syndrome versus with autism: findings from a large-scale US survey

Background As adults with Down syndrome live increasingly longer lives, their adult siblings will most likely assume caregiving responsibilities. Yet little is known about either the sibling relationship or the general functioning of these adult siblings. Using a national, web‐based survey, this study compared adult siblings of individuals with Down syndrome to siblings of individuals with autism in terms of a potential ‘Down syndrome advantage’ and changes across age of the brother/sister with disabilities. Methods Two groups were examined, siblings of persons with Down syndrome (n = 284) and with autism (n = 176). The Adult Sibling Questionnaire measured the number and length of contacts between siblings and their brothers/sisters with disabilities; the warmth, closeness and positiveness of the sibling relationship; and the sibling's overall levels of perceived health, depression and rewards of being a sibling. Results Compared with siblings of brothers/sisters with autism, siblings of brothers/sisters with Down syndrome showed closer, warmer sibling relationships, along with slightly better health, lower levels of depressive symptoms and more contacts. Across age groups of the brother/sister with disabilities, both groups showed lessened contacts, with less close sibling relationships occurring when brothers/sisters with disabilities were aged 30–44 years and 45 years and older (in Down syndrome) and 45 years and older (in autism). Within both groups, closer sibling relationships were associated with more frequent and lengthy contacts, brothers/sisters with disabilities who were better at maintaining friendships and had lower levels of behavioural/emotional problems, and siblings who felt themselves more rewarded by being a sibling to a brother/sister with disabilities. Conclusions In line with earlier work on families of children with disabilities, this study shows an advantage for siblings of adults with Down syndrome, in terms of both sibling relationships and of slightly better health and lessened depressive symptoms. Both joint contacts and close sibling relationships do, however, differ when the brother/sister with disabilities is older. As the first generation of probable caregivers, siblings of persons with Down syndrome who are in their forties, fifties and sixties require increased research attention.     

Cockayne syndrome: siblings with different ultraviolet sensitivity and early onset of manifestations

Siblings of Cockayne syndrome were reported. Both of them had characteristic manifestation of Cockayne syndrome. A 4-year-old boy had been noted to have irritability and nystagmus from the 6th day of his life, and his elder sister, 8 years old, had been diagnosed as cerebral palsy at the age of 6 months. The elder sister lacked photosensitivity clinically. The proband was more severely affected than his elder sister on both cerebral CT-scan and electrophysiological studies. Reduced colony forming ability after ultraviolet exposure is currently considered to be the primary abnormality in Cockayne syndrome. The cells originating from the boy had moderately reduced colony forming ability after ultraviolet irradiation, whereas the cells from his elder sister showed mildly reduced colony forming ability. There may be some relationship between the severity of the symptoms and the colony forming ability. There is a broad spectrum of clinical manifestations in Cockayne syndrome. Further investigations are necessary to clarify the relationship between the cytological abnormalities of Cockayne syndrome and its neurological manifestations.     

Cortical atrophy differentiates Richardson's syndrome from the parkinsonian form of progressive supranuclear palsy

To determine whether brain atrophy differs between the two subtypes of progressive supranuclear palsy (PSP), Richardson's syndrome (PSP‐RS), and PSP parkinsonism (PSP‐P), and whether such atrophy directly relates to clinical deficits and the severity of tau deposition. We compared 24 pathologically confirmed PSP cases (17 PSP‐RS and 7 PSP‐P) with 22 controls from a Sydney brain donor program. Volume loss was analyzed in 29 anatomically discrete brain regions using a validated point‐counting technique, and tau–immunoreactive neurons, astrocytes and oligodendrocytes/threads semiquantified. Correlations between the two pathological measures and the presence or absence of cardinal PSP symptoms were investigated. Cortical atrophy was more severe in PSP‐RS than PSP‐P and affected more frontal lobe regions (frontal pole, inferior frontal gyrus). The supramarginal gyrus was atrophic in both subtypes. Additionally, atrophy of the internal globus pallidus, amygdala, and thalamus was more severe in PSP‐RS. As expected, more severe frontal lobe tau pathology differentiated PSP‐RS from PSP‐P. No correlations were found between the degree of atrophy and severity of tau pathology in any region assessed, or between the severity of atrophy or tau pathology and the presence or absence of cardinal PSP symptoms. Our study shows that thalamocortical atrophy is a defining feature of PSP‐RS, but this atrophy does not correlate with the presence of any specific cardinal clinical feature. Interestingly, there is a disassociation between tau pathology and atrophy in the brain regions affected in PSP‐RS that requires further investigation. © 2010 Movement Disorder Society     

Sleep phenotypes in infants and toddlers with neurogenetic syndromes

BackgroundAlthough sleep problems are well characterized in preschool- and school-age children with neurogenetic syndromes, little is known regarding the early emergence of these problems in infancy and toddlerhood. To inform syndrome-specific profiles and targets for intervention, we compared parent-reported sleep problems in infants and toddlers with Angelman syndrome (AS), Williams syndrome (WS), and Prader–Willi syndrome (PWS) with patterns observed among same-aged typically developing (TD) controls.MethodsMothers of 80 children (18 AS, 19 WS, 19 PWS, and 24 TD) completed the Brief Infant Sleep Questionnaire. Primary dependent variables included (1) sleep onset latency, (2) total sleep duration, (3) daytime and nighttime sleep duration, and (4) sleep problem severity, as measured by both maternal impression and National Sleep Foundation guidelines.ResultsSleep problems are relatively common in children with neurogenetic syndromes, with 41% of mothers reporting problematic sleep and 29% of children exhibiting abnormal sleep durations as per national guidelines. Across genetic subgroups, problems are most severe in children with AS and WS, particularly in relation to nighttime sleep duration. Although atypical sleep is characteristically reported in each syndrome later in development, infants and toddlers with PWS exhibited largely typical patterns, potentially indicating delayed onset of sleep problems in concordance with other medical features of PWS.ConclusionsOur findings suggest that sleep problems in neurogenetic syndromes emerge as early as infancy and toddlerhood, with variable profiles across genetic subgroups. This work underscores the importance of early sleep screenings as part of routine medical care of neurosyndromic populations and the need for targeted, syndrome-sensitive treatment.     

Cough peak flow decline rate predicts survival in patients with amyotrophic lateral sclerosis

Introduction: In this study we investigated the prognostic significance of cough peak flow (CPF) decline rate in patients with amyotrophic lateral sclerosis (ALS). Methods: Thirty-four patients with ALS participated in our investigation. We examined CPF, forced vital capacity (FVC), body mass index, and the revised ALS Functional Rating Scale (ALSFRS-R), and followed patients to death, tracheostomy, or non-invasive ventilator dependency. We analyzed the relationship between the rate of decline of each parameter and survival prognosis. Results: The CPF decline rate significantly correlated with the decline rates of the ALSFRS-R bulbar score (P < 0.0001) and FVC (P < 0.0001). Patients with a CPF decline rate ≥25% had shorter overall survival (P < 0.0001). Cox model multivariate analyses showed that the CPF decline rate was an independent prognostic factor for survival (P = 0.021). Discussion: The CPF decline rate reflects the progression of bulbar and respiratory dysfunction and predicts survival. Muscle Nerve 59 :168–173, 2019     

Preschool children with intellectual disability: syndrome specificity, behaviour problems, and maternal well-being

Background Children with intellectual disability (ID) are at heightened risk for behaviour problems and diagnosed mental disorder. Likewise, mothers of children with ID are more stressed than mothers of typically developing children. Research on behavioural phenotypes suggests that different syndromes of ID may be associated with distinct child behavioural risks and maternal well-being risks. In the present study, maternal reports of child behaviour problems and maternal well-being were examined for syndrome-specific differences. Methods The present authors studied the early manifestation and continuity of syndrome-specific behaviour problems in 215 preschool children belonging to 5 groups (typically developing, undifferentiated developmental delays, Down syndrome, autism, cerebral palsy) as well as the relation of syndrome group to maternal well-being. Results At age 3, children with autism and cerebral palsy showed the highest levels of behaviour problems, and children with Down syndrome and typically developing children showed the lowest levels. Mothers of children with autism reported more parenting stress than all other groups. These syndrome-specific patterns of behaviour and maternal stress were stable across ages 3, 4 and 5 years, except for relative increases in behaviour problems and maternal stress in the Down syndrome and cerebral palsy groups. Child syndrome contributed to maternal stress even after accounting for differences in behaviour problems and cognitive level. Conclusions These results, although based on small syndrome groups, suggest that phenotypic expressions of behaviour problems are manifested as early as age 3. These behavioural differences were paralleled by differences in maternal stress, such that mothers of children with autism are at elevated risk for high stress. In addition, there appear to be other unexamined characteristics of these syndromes, beyond behaviour problems, which also contribute to maternal stress.     

Cardiac manifestation is evident in chorea-acanthocytosis but different from McLeod syndrome

IntroductionWe aimed to study the various cardiac manifestations of the two core neuroacanthocytosis (NA) syndromes, namely chorea-acanthocytosis (ChAc) and McLeod syndrome (MLS). So far, cardiac involvement has been described as specific feature only for MLS.MethodsWe studied six patients with ChAc (mean age 44.5 years, five men, one woman) and six patients with MLS (mean age 57.1 years, all men). Cardiac evaluation included echocardiography and/or cardiac magnetic resonance imaging (cardiac MRI), 24-h ECG-recording and examination of cardiac biomarkers.ResultsCardiac involvement of ChAc was found in four of six patients. Two patients showed mildly reduced left ventricular ejection fraction (LVEF), two other patients mild to moderate left ventricular (LV) dilatation. Neither an increase in ventricular ectopic beats nor ventricular tachycardia were evident in ChAc. Four of five MLS patients showed left ventricle dilatation and reduced left ventricular ejection fraction (LVEF). Two of these, in addition, had critical ventricular tachycardia. High sensitive troponin T was elevated in all patients, for whom data were available (n = 10). In contrast, elevation of high sensitive troponin I was found in one of six ChAc and one of two MLS patients.ConclusionFor the first time, we reveal cardiac involvement in a cohort of six ChAc patients, while the risk to develop heart failure seems lower than in MLS. Our study confirms the malignant nature of MLS in terms of ventricular arrhythmias and progression to advanced heart failure. Herein, we define disease-specific recommendations for cardiac assessment in both conditions.     

Infantile spasms syndrome,West syndrome and related phenotypes: What we know in 2013

The current spectrum of disorders associated to clinical spasms with onset in infancy is wider than previously thought; accordingly, its terminology has changed. Nowadays, the term Infantile spasms syndrome (ISs) defines an epileptic syndrome occurring in children younger than 1 year (rarely older than 2 years), with clinical (epileptic: i.e., associated to an epileptiform EEG) spasms usually occurring in clusters whose most characteristic EEG finding is hypsarrhythmia [the spasms are often associated with developmental arrest or regression]. The term West syndrome (WS) refers to a form (a subset) of ISs, characterised by the combination of clustered spasms and hypsarrhythmia on an EEG and delayed brain development or regression [currently, it is no longer required that delayed development occur before the onset of spasms]. Less usually, spasms may occur singly rather than in clusters [infantile spasms single-spasm variant (ISSV)], hypsarrhythmia can be (incidentally) recorded without any evidence of clinical spasms [hypsarrhythmia without infantile spasms (HWIS)] or typical clinical spasms may manifest in absence of hypsarrhythmia [infantile spasms without hypsarrhythmia (ISW)]. There is a growing evidence that ISs and related phenotypes may result, besides from acquired events, from disturbances in key genetic pathways of brain development: specifically, in the gene regulatory network of GABAergic forebrain dorsal–ventral development, and abnormalities in molecules expressed at the synapse. Children with these genetic associations also have phenotypes beyond epilepsy, including dysmorphic features, autism, movement disorders and systemic malformations. The prognosis depends on: (a) the cause, which gives origin to the attacks (the complex malformation forms being more severe); (b) the EEG pattern(s); (c) the appearance of seizures prior to the spasms; and (d) the rapid response to treatment. Currently, the first-line treatment includes the adrenocorticotropic hormone ACTH and vigabatrin. In the near future the gold standard could be the development of new therapies that target specific pathways of pathogenesis. In this article we review the past and growing number of clinical, genetic, molecular and therapeutic discoveries on this expanding topic.     

Familial Lennox‐Gastaut syndrome in male siblings with a novel DCX mutation and anterior pachygyria

Lennox‐Gastaut syndrome (LGS) has numerous causes, but only rarely has familial recurrence been observed. We studied a family in which three male members had severe epilepsy and intellectual disability. The proband had seizure onset at 7 years of age with atonic, myoclonic, atypical absence, and tonic seizures with slow spike‐wave on electroencephalography (EEG). One living sibling had a similar clinical pattern. One deceased sibling was known to have had seizures with intellectual disability. Neuroimaging revealed anterior predominant pachygyria. DNA sequencing of the gene doublecortin (DCX) on the X chromosome revealed a novel missense mutation in the two living affected male siblings. The occurrence of three affected male family members with proven or suspected LGS in this family was puzzling and only solved by a combination of magnetic resonance (MR) and molecular genetics evaluations. This finding provided essential information for genetic counseling.     

Bilateral brachial plexus palsy and right Horner syndrome due to congenital cervicothoracal syringomyelia

Syringomyelia (SM) is a disorder in which a cyst forms within the spinal cord. This cyst, called a syrinx, expands and elongates over time, destroying the center of the cord. Horner syndrome is an infrequent illness caused by a lesion of the cervical sympathetic nerve fiber. Its clinical features are facial anhidrosis, ptosis, miosis, and hypochromia iridis of the affected side. A full-term male newborn infant was admitted with weakness in bilateral upper extremities and narrowing of the palpebral fissure on the right side. Ophthalmologic examination revealed a smaller right pupil. Muscle power in bilateral upper limbs was 1/5. Chest X-ray and cranial magnetic resonance imaging were normal. Magnetic resonance imaging of the cervicothoracic spine showed SM at C4-T2 level. Electromyographic examination revealed bilateral brachial plexus palsy. The diagnosis was of brachial plexus palsy and congenital Horner syndrome due to congenital cervicothoracic SM. According to our best knowledge, this association has not been reported in the literature.