Atypical clinical course in two patients with GNB1 variants who developed acute encephalopathy

IntroductionVariants in the GNB1 gene, which encodes the β1 subunit of a trimeric G protein, can cause moderate to severe psychomotor retardation. Acute encephalopathies have also been observed in patients with central nervous system abnormalities; however, severe neurological sequelae have not previously been reported.Case presentationsPatient 1 was a Japanese female with a de novo GNB1 variant (c.284 T > C). At 8 months old she contracted influenza A and developed generalized convulsions. In the acute phase, brain magnetic resonance imaging (MRI) findings indicated acute encephalopathy; diffuse cerebral atrophy was present 1 month later. Although multidisciplinary treatment was administered, she had severe neurological sequelae including spastic tetraplegia, severe intellectual disabilities, and refractory epilepsy. Patient 2 was a Japanese male with a de novo GNB1 variant (c.239 T > C). He experienced an unexplained respiratory arrest aged 17 years; refractory convulsions developed. Brain MRI at 1 month showed bilateral basal ganglia high intensities; at 3 months, diffuse cerebral cortex and white matter atrophy was observed. Despite multidisciplinary treatment, he developed severe spastic tetraplegia and mental regression.DiscussionWe report two patients with GNB1 variants who had acute lesions on brain MRI and unexpected disease courses. In such patients with acute neurological deterioration, multidisciplinary treatment is required; patients should also be carefully observed for progression to acute encephalopathy.     

Mutation of breast cancer susceptibility genes increases cerebral microbleeds: A pilot study

ObjectivesGrowing evidence suggests breast cancer susceptibility gene (BRCA) mutations may augment cerebrovascular risk factors. With this influence in mind, we aimed to identify if BRCA mutations increased the prevalence of cerebral small vessel disease (CSVD).Methods and MaterialsWe performed a retrospective cross-sectional analysis of adults undergoing malignancy evaluation with confirmed BRCA mutations compared to BRCA wildtype individuals. A standard-of-care brain MRI was reviewed. Chi-squared or Fisher's, Wilcoxon rank-sum and the Student's t-test analyses were used when appropriate. Adjusted logistic regression models were fit to calculate odds ratio. Multicollinearity was tested by variance inflation factor calculation and for goodness-of-fit via the Hosmer-Lemeshow test.ResultsOf 116 individuals, 44.8% (52/116) carried a BRCA mutation. Demographic and cerebrovascular risk factors did not differ. Cerebral microbleeds were more common in those with BRCA mutation: [32.7% (17/52) vs. 17.2% (11/64), p = 0.05] with an adjusted odds ratio of 2.8 (95%CI 1.08-6.89, p = 0.03). Other markers of CSVD were similar amongst the cohort.ConclusionsWe identified a nearly 3-fold increase in identified cerebral microbleed in those with BRCA mutations compared with BRCA wildtype individuals suggestive of an interaction between the BRCA gene and cerebral microbleed formation. Further studies are needed to confirm our findings and to understand clinical implications.     

The GABAA Receptor γ2 Subunit (R43Q) Mutation in Febrile Seizures

BackgroundFebrile seizure is the most common form of childhood seizure. Although its exact cause is unclear, many researchers emphasize the importance of its genetic predisposition. Recent genetic studies revealed the importance of the mutations of the gamma-aminobutyric acid A receptor as the etiology of the febrile seizures. R43Q mutation affecting the γ2-subunit N-terminal domain has been related to childhood absence epilepsy and febrile seizure.MethodsWe investigated R43Q mutations of the GABRG2 gene, located on the long arm of chromosome 5 encoding the γ2-subunit of the gamma-aminobutyric acid A receptor. We studied 44 patients with febrile seizure and 49 children without any febrile seizure who were admitted to our clinic.ResultsWe found that 36% of our patient group, the children who experienced febrile convulsions, had heterozygous R43Q mutation. Statistical studies revealed that heterozygous R43Q mutation of gamma-aminobutyric acid A receptor γ2 subunit was higher in the study group than in the control group (P < 0.01).ConclusionsHeterozygous gamma-aminobutyric acid A receptor γ2 subunit (R43Q) mutation may have an effect in the development of febrile seizures.     

Risk factors for acute symptomatic cerebral infarctions after spontaneous supratentorial intra-cerebral hemorrhage

Cerebral infarctions are unfavorable outcomes of spontaneous intra-cerebral hemorrhage (ICH). To date, there have been no reports on risk factors that are predictive of acute symptomatic cerebral infarctions. With the aim of determining the potential risk factors that are predictive of acute symptomatic cerebral infarctions in patients with spontaneous supratentorial ICH, we have retrospectively evaluated 212 hospitalized patients with spontaneous ICH and compared those who developed a complicated cerebral infarction with those who did not. Cerebral infarctions developed in 8.02% (17/212) of the patient cohort. Neuro-imaging findings between the two patient groups revealed that the presence of intra-ventricular hemorrhage (IVH), hydrocephalus, and the median value of intra-cranial hematoma on admission were significant factors, as well as neurosurgical intervention. However, the multiple logistic regression analysis revealed that only the presence of IVH had an odds ratio of 4.7 (95% confidence interval 0.06–0.75; p = 0.016) in patients with acute symptomatic infarctions. The results indicate that the presence of IVH may imply a danger of cerebrovascular complications when treating spontaneous supratentorial ICH during hospitalization. The frequency of acute symptomatic cerebral infarctions in patients with spontaneous supratentorial ICH is high (8%) and is associated with longer hospitalization and worse outcome.     

Triple bypass for multisystem smooth muscle dysfunction syndrome due to Arg179His ACTA2 mutation

Missense mutations in the smooth muscle-specific isoform of the alpha-actin (ACTA2) gene, which encodes smooth muscle actin, congenitally cause systemic smooth muscle dysfunction, leading to multiple systemic smooth muscle dysfunction syndrome. This disease is often diagnosed through the development of congenital mydriasis, patent ductus arteriosus, or thoracic aortic aneurysm at a young age. Some patients develop cerebrovascular lesions, also known as ACTA2 cerebral arteriopathy, which cause ischemic stroke and require surgical revascularization. However, an effective and safe treatment has not yet been established owing to the rarity of the disease. Furthermore, most reports of this disease involve children, with only a few reports on adults and few detailed reports on treatment outcomes published to date. We report a 46-year-old woman with ACTA2 cerebral arteriopathy caused by Arg179His, the most common mutation in this disease; she is the oldest patient reported with this disease to the best of our knowledge. The patient was diagnosed with multiple systemic smooth muscle dysfunction syndrome and ACTA2 cerebral arteriopathy after experiencing a stroke in the right cingulate gyrus. She underwent direct triple bypass with three anastomoses of the right superficial temporal artery to the middle and anterior cerebral arteries. She developed an ischemic stroke as a postoperative complication.The efficacy and safety of this procedure have not been clearly confirmed owing to the frailty of the donor superficial temporal artery and the poor development of collateral circulation; however, direct bypass should be considered a treatment option for patients experiencing progressive multiple strokes.     

Cerebral arteriopathy and ischemic stroke in a pediatric MYH11 patient

ObjectivesMutations in the MYH11 gene result in smooth muscle cell dysfunction and are associated with familial thoracic aortic aneurysms and dissection. We describe a pediatric patient with a stroke and a pathogenic MYH11 IVS32G>A mutation, and a phenotype similar to ACTA2.MethodsA proband girl with an acute ischemic stroke underwent genetic analysis and 7T high-resolution MRI.ResultsA 12-year-old girl presented with a right middle cerebral artery occlusion. She received thrombolysis and underwent mechanical thrombectomy. An extensive stroke work-up was negative. A three-generation pedigree showed a splice site mutation of MYH11 IVS32G>A of the proband and three more family members. A 7T-MRI showed “broomstick-like” straightening of distal arterial segments, a V-shaped anterior corpus callosum and a post-stroke cystic area of encephalomalacia. This vascular appearance and parenchymal abnormalities typically present in patients with an ACTA2 phenotype. 7T-MRI also demonstrated thickening of the right middle cerebral arterial wall.DiscussionThis case suggests that MYH11 patients may have a similar angiographic and brain parenchymal phenotype to patients with ACTA2 mutations. This is the first report of arterial wall thickening in a MYH11 stroke patient using 7T-MRI. Patients with MYH11 mutations may display a focal cerebral steno-occlusive arteriopathy that may lead to stroke.     

Cerebral arteriopathy associated with heterozygous Arg179Cys mutation in the ACTA2 gene: Report in 2 newborn siblings

Mutations in the ACTA2 gene lead to a multisystemic smooth muscle dysfunction syndrome that causes vascular disease, congenital mydriasis, and variable presentation of urinary and gastrointestinal problems. The heterozygous Arg179 mutation is associated with a distinctive cerebrovascular phenotype. We report the cases of two newborn siblings with heterozygous ACTA2 Arg179Cys substitution and provide neuroimaging exams that demonstrate the distinctive cerebrovascular phenotype, also associated with variable degree of hypoplasia of the vertebro-basilar circulation as well as hypoxic-ischemic lesions.     

Expanding the phenotype of COL4A1-related disorders—Four novel variants

ObjectiveCOL4A1 variant causes severe central nervous system (CNS) anomalies, including hydranencephaly. However, the pathogenic mechanism underlying the COL4A1 phenotype remains unclear. Here, we report de novo COL4A1 variants in four Japanese patients with typical or rare CNS involvement and exhibiting diverse phenotypes.MethodsWe identified and enrolled four patients with white matter abnormalities and cerebral structural defects suggestive of cerebrovascular disease. Genetic analysis was performed using panel sequencing.ResultsAll the patients were perinatally asymptomatic during the infantile period but exhibited developmental delay and growth retardation later. All the patients exhibited CNS symptoms, including psychomotor disability, spastic paralysis, and epilepsy. Brain magnetic resonance imaging revealed hydranencephaly (n = 1), ventriculomegaly (n = 4) associated with cerebral hemorrhage, and atretic encephalocele (n = 1). Three patients had developed congenital cataract, while two had hematuria. We identified two COL4A1 missense variants [exon32:c.2555G > A p.(Gly852Asp), exon40:c.3407G > A p.(Gly1136Asp)] and two in frame variants [exon32:c.2603_2609delinsATCCTGA p.(Ala868_Gly870delinsAspProGlu), exon36:c.3054delinsTGTAGAT p.(Leu1018delinsPheValAsp)]. The in frame variants were associated with severe CNS anomalies, hydranencephaly, and severe ventriculomegaly. Atretic encephalocele has never been reported in individuals with COL4A1 variants.ConclusionsOur findings suggest that COL4A1 variants cause variable CNS symptoms. Association between clinical phenotypes and each COL4A1 variant would clarify their underlying etiologies.     

De Novo Cerebral Microbleeds and Cognitive Decline in Cerebral Hyperperfusion After Direct Revascularization for Adult Moyamoya Disease

ObjectivesAdult patients with moyamoya disease (MMD) occasionally develop cognitive decline due to cerebral hyperperfusion following direct revascularization surgery. However, how the hyperperfusion phenomenon contributes to declines in cognitive function remains unclear. The present supplementary analysis of a prospective study aimed to determine whether cerebral hyperperfusion following direct revascularization surgery for adult MMD with ischemic presentation and misery perfusion leads to development of de novo cerebral microbleeds (CMBs) and whether postoperative cognitive decline is related to these CMBs.Materials and MethodsIn total, 32 patients who underwent direct revascularization surgery also underwent T2*-weighted magnetic resonance imaging (T2*WI) and neuropsychological testing before and 2 months after surgery. Development of cerebral hyperperfusion and hyperperfusion syndrome following surgery was defined based on brain perfusion single-photon emission computed tomography (SPECT) findings and clinical symptoms.ResultsCerebral hyperperfusion on brain perfusion SPECT (95% confidence interval [CI], 1.1–10.8; p = 0.0175) or cerebral hyperperfusion syndrome (95%CI, 1.3–15.3; p = 0.0029) was significantly associated with postoperatively increased CMBs on T2*WI. Postoperatively increased CMBs were significantly associated with postoperative cognitive decline (95%CI, 1.8–20.4, p = 0.0041). For patients with cerebral hyperperfusion on brain perfusion SPECT, the incidence of postoperative cognitive decline was significantly greater in patients with than in those without postoperatively increased CMBs (p = 0.0294).ConclusionsCerebral hyperperfusion following direct revascularization surgery for adult MMD with ischemic presentation and misery perfusion contributes to the development of de novo CMBs and postoperative cognitive decline is related to these CMBs.     

Pediatric Cerebral Palsy in Botswana: Etiology,Outcomes, and Comorbidities

BackgroundCerebral palsy is the most common cause of motor dysfunction in children worldwide and is often accompanied by multiple comorbidities. Although cerebral palsy has been studied extensively in high-resource settings, there are few published studies on cerebral palsy etiology, outcomes and comorbidities in low-resource settings.MethodsChildren with cerebral palsy were prospectively enrolled from inpatient and outpatient settings at a referral center in Gaborone, Botswana, in a cross-sectional study conducted from 2013 to 2014. Cerebral palsy etiology, outcomes, and comorbidities were determined through caregiver interviews, review of medical records, and direct physical examination.ResultsSixty-eight children with cerebral palsy were enrolled. Subjects were 41% male, with a median age of 4 years (interquartile range = 2 to 7). The most common etiologies for cerebral palsy in our cohort were intrapartum hypoxic events (18%), postnatal infections (15%), prematurity (15%), focal ischemic strokes (10%), and prenatal infections (10%). Severe motor impairment was common, with the most severe category present in 41%. The predominant comorbidities were cognitive impairment (84%), epilepsy (77%), and visual impairment (46%).ConclusionsCerebral palsy in Botswana has different etiologies and is associated with poorer outcomes and higher prevalence of comorbidities than what has been reported in high-resource settings. Further studies are necessary to determine optimal preventative and treatment strategies in this population.     

Enfermedad moyamoya en México. Experiencia institucional

IntroductionMoyamoya disease (MD) is a progressive, occlusive disease of the arteries of the anterior cerebral circulation that may cause ischaemia or haemorrhage. Patient management aims to prevent new cerebrovascular events through surgical revascularisation and/or pharmacological treatment.MethodsWe studied a series of 17 patients with MD (n = 14) or moyamoya syndrome (n = 3), who were evaluated between January 1989 and December 2016; 11 patients were women and 6 were men. Thirteen patients had definitive MD (76%), one had unilateral MD (5.2%), and 3 had moyamoya syndrome (18%). The condition manifested as intraparenchymal haemorrhage (in 35.2% of patients), brain ischaemia (29.4%), subarachnoid haemorrhage (17.6%), seizures (11.7%), and headache with no associated haemorrhage (one patient).ResultsTen patients (58.8%) underwent revascularisation and 7 (41.2%) received pharmacological treatment. All patients were evaluated with the modified Rankin Scale (mRs) at admission and at the last consultation; mRs scores were significantly lower in the group undergoing surgery (P < .04). During follow-up, none of the patients undergoing revascularisation experienced recurrences, whereas 2 patients receiving pharmacological treatment did experience a new vascular event (one ischaemic and one haemorrhagic) (P < .05). No significant differences were observed between the treatment outcomes of different revascularisation techniques.ConclusionsAlthough our population has different demographic characteristics from those of other non-Asian populations, ours is the largest published series of Hispanic individuals with MD. Our results support the use of revascularisation procedures to improve these patients’ neurological status and to prevent new cerebrovascular events.     

The eldest case of MICPCH with CASK mutation exhibiting gross motor regression

BackgroundMICPCH is manifested as microcephaly associated with pontocerebellar hypoplasia and global developmental delay but developmental regression has never been reported. We describe the detailed clinical history of a woman with intellectual disability and microcephaly with pontine and cerebellar hypoplasia (MICPCH) with a CASK mutation who exhibited gross motor regression after adolescence.Case: The patient experienced severe motor and intellectual developmental delay with microcephaly from infancy. The initial diagnosis was Rett syndrome based on her clinical features, including hand stereotypes and the absence of structural abnormality on magnetic resonance imaging (MRI) performed at the age of 5 years. Although gross motor abilities developed slowly and she could walk independently, she never acquired speech or understanding of languages. After adolescence, her motor ability gradually regressed so that she was unable to stand without support and moved with a wheelchair. At the age of 31 years, because of her atypical clinical course for Rett syndrome, whole exome sequencing was performed, which revealed a de novo heterozygous c.2068 + 1G > A mutation in the CASK gene (NM_001126055). Brain MRI revealed mild pontocerebellar hypoplasia compatible with the clinical phenotype of MICPCH.DiscussionThis case suggests that MICPCH with a CASK mutation might cause developmental regression after adolescence and might be regarded as a neurodegenerative disorder.     

Cap myopathy caused by a mutation of the skeletal alpha-actin gene ACTA1

Cap myopathy is a congenital myopathy with cap-like structures under the sarcolemma. Mutations in TPM2 and TPM3 genes have been reported in cap myopathy so far.We report a newborn boy with persistent profound weakness who required gastro-jejunal tube feeding, tracheostomy and life-long ventilation until he died at 5 years of age. Muscle biopsy at 5 weeks of age was uninformative. Repeat biopsy at 4.5 years revealed subsarcolemmally located caps that were immunopositive for alpha-actinin, actin and to some extent, desmin. EM confirmed loosely arranged thin filaments and paucity of thick filaments. Molecular analysis of ACTA1 gene identified a novel de novo Met47Val mutation.In addition to a new ACTA1 gene mutation, our case emphasizes the genetic heterogeneity of cap myopathy and its association with ACTA1 gene as well as the importance of repeat muscle biopsy in patients with undiagnosed muscle weakness.     

Prediction of outcome following hypoxia/ischaemia in the human infant using cerebral impedance

ObjectiveChanges in cerebral impedance in the newborn piglet are able to discriminate, within 1–2 h of acute hypoxia, between animals which will have a good neurological outcome, and those who have suffered more severe hypoxia resulting in poor outcome. The aim of this study was to determine if cerebral impedance could be used to identify those human infants with an encephalopathy following acute hypoxia who subsequently have a poor neurological outcome. It is these infants who may benefit most from neural rescue treatment.MethodsTwenty-four newborn term infants with evidence of severe acute intrapartum hypoxia and encephalopathy were studied. Bioimpedance spectroscopy was commenced as soon as possible after birth and repeated every 30 min until the infant was 12 h old. Neurodevelopmental outcome was assessed at 12 months of age.ResultsAlthough cerebral impedance was different to control values, there was no significant difference in cerebral impedance between hypoxic babies with normal and those with abnormal development.ConclusionCerebral impedance was increased in hypoxic babies, as predicted from animal data, but the method was not suitable for discrimination of outcome.SignificanceCerebral impedance is not useful for early identification of infants who subsequently have a poor outcome after acute intrapartum hypoxia and who may benefit from neural rescue treatment.     

Moderate-to-severe obstructive sleep apnea is associated with cerebral small vessel disease

BackgroundCerebral small vessel disease (SVD) is associated with increased risk of cerebral infarction and hemorrhage. Obstructive sleep apnea (OSA) is known to increase the risk of cerebrovascular disease. This study aimed to investigate the association between cerebral SVD and severity of OSA.MethodsA total of 170 patients were included from the patient registry at the present Sleep Center; these patients underwent both magnetic resonance imaging (MRI) of the brain and polysomnography (PSG) for suspected OSA. The presence and burden of white matter hyperintensities (WMHs), asymptomatic lacunar infarctions (ALIs), cerebral microbleeds (CMBs), and perivascular spaces (PVSs) were determined by MRI, and their relationships with the apnea–hypopnea index (AHI), as determined by PSG, were investigated.ResultsAmong the 170 patients, 25 (14.7%) had high-grade WMHs, 21 (12.4%) had ALIs, 21 (12.4%) had CMBs, and 34 (20.0%) had high-grade PVSs. In the multivariable analysis, after adjusting for factors including age, sex, and other variables for which p <0.1 in univariable analysis (hypertension, diabetes mellitus, previous stroke, minimal SaO₂ and arousal index), moderate-to-severe OSA was associated with high-grade WMHs (odds ratio [OR] 4.72; 95% confidence interval [CI] 1.14–19.47), CMBs (OR 3.47; 95% CI 0.89–15.18), or high-grade PVSs (OR 3.64; 95% CI 1.02–13.01), but not with ALIs. The total SVD score was independently associated with increased AHI (p = 0.017), particularly in patients with moderate-to-severe OSA (β [standard error] = 0.448 (0.204), p = 0.030].ConclusionModerate-to-severe OSA is positively associated with multiple indicators of cerebral SVD, including WMHs, CMBs, and PVSs.     

Cerebral Infarction in Adults with Bacterial Meningitis

Background

To evaluate clinical features and prognostic factors of cerebral infarctions in adults with community-acquired bacterial meningitis.

Method

An observational cross-sectional study, including 696 patients of whom 174 had cerebral infarction, from a prospective nationwide cohort of community-acquired bacterial meningitis (period, 1998?C2002), confirmed by culture of cerebral spinal fluid (CSF) in patients aged over 16?years. Two investigators independently determined the presence of infarction.

Result

Cerebral infarction occurred in 174 episodes (25%), with a high inter-rater agreement for determining the presence of cerebral infarction (kappa 0.95). Cerebral infarctions occurred in 128 of 352 patients (36%) with pneumococcal meningitis, in 22 of 257 (9%) with meningococcal meningitis and in 24 of 87 patients (28%) with meningitis caused by other bacteria. Patients with infarctions were older (P?P?=?0.001) or an immunocompromised state (P?=?0.003) compared to those without infarction. Patients with infarctions presented with lower scores on the Glasgow Coma Scale (P?P?=?0.001), and higher serum erythrocyte sedimentation rate (ESR) (P?P?Conclusion Cerebral infarction is a common and severe complication in adults with community-acquired bacterial meningitis. Preventing cerebral infarctions will be important in reducing the high morbidity and mortality rate in adults with community-acquired bacterial meningitis.     

Superficial temporal artery–middle cerebral artery bypass for ischemic atherosclerotic middle cerebral artery disease

Most recent studies on the effectiveness of cerebral revascularization have focused on the treatment of atherosclerotic internal carotid artery occlusive disease. The goal of the present study was to assess neurological function in 11 severe atherosclerotic middle cerebral artery (MCA) disease patients with transient ischemic attacks (TIAs) and hemodynamic compromise and determine the efficacy of superficial temporal artery–middle cerebral artery (STA-MCA) bypass. There were eight patients with MCA occlusion and three with severe MCA stenosis. After the bypass procedure, all 11 patients experienced reduction in TIAs and no stroke during a mean follow-up of 34.36 months. Surgical revascularization increased regional cerebral blood flow (mL/100 g/min) from a mean of (± standard deviation) 25.9 ± 7.39 preoperatively to 32.3 ± 7.72 postoperatively, and improved regional cerebrovascular reactivity from ?6.42% ± 14.61% to 30.14% ± 23.93% (p = 0.014) in the eight patients with atherosclerotic MCA occlusion. Our findings demonstrated the benefit of STA-MCA bypass for patients with medically refractory and symptomatic atherosclerotic MCA occlusion with hemodynamic compromise.     

Long-term changes in electroencephalogram findings in a girl with a nonsense SMC1A variant: A case report

IntroductionPathogenic truncating variants in SMC1A, which is located on chromosome Xp11.2, are known to cause infantile-onset epilepsy and severe intellectual disability in girls. Several studies have reported a correlation between SMC1A truncations and seizure clustering; however, the associated electroencephalogram (EEG) patterns remain largely unknown.Case presentationWe investigated an 12-year-old girl who had developed epilepsy at the age of 4 months. The patient experienced unknown onset, tonic-clonic seizures that occurred in clusters several times a week. Her interictal EEG at the age of 2 years showed paroxysmal, generalized, high-amplitude slow waves, whereas epileptiform discharges were scarce. The patient’s interictal EEG gradually deteriorated; at the age of 11 years, diffuse continuous spike-and-wave discharges were predominantly observed in the left temporal region and were particularly obvious in the awake state. Although the unknown onset, tonic seizures occurring weekly persisted under multiple antiepileptic medications, the patient did not experience seizure clustering since the age of 9 years. Whole-genome sequencing revealed a de novo known nonsense variant in SMC1A (c.2923C > T, p.R975*).ConclusionOur patient presented with a mild abnormality in the interictal EEG during infancy and early childhood despite frequent seizure clustering. Notably, the patient’s EEG findings gradually deteriorated over time, which was inconsistent with the amelioration of seizure clustering.     

Early motor development of children with a congenital cytomegalovirus infection

BackgroundCongenital cytomegalovirus (cCMV) infection is the most important etiology of non-hereditary childhood hearing loss and an important cause of neurodevelopmental delay. The current study aimed to investigate the early motor development of symptomatic and asymptomatic cCMV infected children with and without sensorineural hearing loss (SNHL).MethodsSixty-four children with a cCMV infection, without cerebral palsy, were compared to a control group of 107 normal hearing children. They were assessed around the ages of 6, 12, and 24 months with the Peabody Developmental Motor Scales-2 (PDMS-2), Alberta Infant Motor Scales (AIMS), and Ghent Developmental Balance Test (GDBT). The cCMV infected children were subdivided into a symptomatic (n = 26) and asymptomatic cCMV group (n = 38) but also into a cCMV group with SNHL (n = 19) and without SNHL (n = 45).ResultsSymptomatic cCMV infected children and cCMV infected children with SNHL performed significantly weaker for all gross motor outcome measures.ConclusionA congenital CMV infection is a risk factor for a delay in the early motor development. Follow-up will be necessary to gain insight into the exact cause of this motor delay and to define the predictive value of early motor assessment of cCMV infected children.     

A de novo dominant mutation in ACTA1 causing congenital nemaline myopathy associated with a milder phenotype: Expanding the spectrum of dominant ACTA1 mutations

We describe the presentation and six-year follow up of a child with nemaline myopathy due to a de novo mutation in the skeletal muscle α-actin gene (ACTA1) characterized by dramatic improvement during the early childhood years. The presentation in this female patient was infantile-onset weakness in the facial, bulbar, respiratory and neck flexor muscles. A six-year follow-up revealed continued progressive improvement in her muscle strength. Based upon the histopathologic and ultrastructural features of nemaline rod disease, ACTA1 was sequenced. This revealed a mutation in exon 4 of ACTA1 (c.557A>G). Our report further expands the phenotypic spectrum associated with ACTA1 mutations. Although it is difficult to infer any genotype–phenotype correlation, this report stimulates the discussion regarding the pathophysiologic mechanism of the clinical improvement seen in some patients with ACTA1 mutations.