Nomazulu Dlamini

Mutations in RYR1 are a common cause of exertional myalgia and rhabdomyolysis

Mutations in the skeletal muscle ryanodine receptor (RYR1) gene are a common cause of neuromuscular disease, ranging from various congenital myopathies to the malignant hyperthermia (MH) susceptibility trait without associated weakness. We sequenced RYR1 in 39 unrelated families with rhabdomyolysis and/or exertional myalgia, frequent presentations in the neuromuscular clinic that often remain unexplained despite extensive investigations. We identified 9 heterozygous RYR1 mutations/variants in 14 families, 5 of them (p.Lys1393Arg; p.Gly2434Arg; p.Thr4288_Ala4290dup; p.Ala4295Val; and p.Arg4737Gln) previously associated with MH. Index cases presented from 3 to 45 years with rhabdomyolysis, with or without exertional myalgia (n=12), or isolated exertional myalgia (n=2). Rhabdomyolysis was commonly triggered by exercise and heat and, less frequently, viral infections, alcohol and drugs. Most cases were normally strong and had no personal MH history. Inconsistent additional features included heat intolerance, and cold-induced muscle stiffness. Muscle biopsies showed mainly subtle changes. Familial RYR1 mutations were confirmed in relatives with similar or no symptoms. These findings suggest that RYR1 mutations may account for a substantial proportion of patients presenting with unexplained rhabdomyolysis and/or exertional myalgia. Associated clinico-pathological features may be subtle and require a high degree of suspicion. Additional family studies are paramount in order to identify potentially MH susceptible relatives.

Arteriopathy Diagnosis in Childhood Arterial Ischemic Stroke Results of the Vascular Effects of Infection in Pediatric Stroke Study

Background and Purpose Although arteriopathies are the most common cause of childhood arterial ischemic stroke (AIS), and the strongest predictor of recurrent stroke, they are difficult to diagnose. We studied the role of clinical data and follow-up imaging in diagnosing cerebral and cervical arteriopathy in children with AIS.Background and Purpose— Although arteriopathies are the most common cause of childhood arterial ischemic stroke, and the strongest predictor of recurrent stroke, they are difficult to diagnose. We studied the role of clinical data and follow-up imaging in diagnosing cerebral and cervical arteriopathy in children with arterial ischemic stroke. Methods— Vascular effects of infection in pediatric stroke, an international prospective study, enrolled 355 cases of arterial ischemic stroke (age, 29 days to 18 years) at 39 centers. A neuroradiologist and stroke neurologist independently reviewed vascular imaging of the brain (mandatory for inclusion) and neck to establish a diagnosis of arteriopathy (definite, possible, or absent) in 3 steps: (1) baseline imaging alone; (2) plus clinical data; (3) plus follow-up imaging. A 4-person committee, including a second neuroradiologist and stroke neurologist, adjudicated disagreements. Using the final diagnosis as the gold standard, we calculated the sensitivity and specificity of each step. Results— Cases were aged median 7.6 years (interquartile range, 2.8–14 years); 56% boys. The majority (52%) was previously healthy; 41% had follow-up vascular imaging. Only 56 (16%) required adjudication. The gold standard diagnosis was definite arteriopathy in 127 (36%), possible in 34 (9.6%), and absent in 194 (55%). Sensitivity was 79% at step 1, 90% at step 2, and 94% at step 3; specificity was high throughout (99%, 100%, and 100%), as was agreement between reviewers (&kgr;=0.77, 0.81, and 0.78). Conclusions— Clinical data and follow-up imaging help, yet uncertainty in the diagnosis of childhood arteriopathy remains. This presents a challenge to better understanding the mechanisms underlying these arteriopathies and designing strategies for prevention of childhood arterial ischemic stroke.

Risk of Recurrent Arterial Ischemic Stroke in Childhood A Prospective International Study

Background and Purpose— Published cohorts of children with arterial ischemic stroke (AIS) in the 1990s to early 2000s reported 5-year cumulative recurrence rates approaching 20%. Since then, utilization of antithrombotic agents for secondary stroke prevention in children has increased. We sought to determine rates and predictors of recurrent stroke in the current era. Methods— The Vascular Effects of Infection in Pediatric Stroke (VIPS) study enrolled 355 children with AIS at 37 international centers from 2009 to 2014 and followed them prospectively for recurrent stroke. Index and recurrent strokes underwent central review and confirmation, as well as central classification of causes of stroke, including arteriopathies. Other predictors were measured via parental interview or chart review. Results— Of the 355 children, 354 survived their acute index stroke, and 308 (87%) were treated with an antithrombotic medication. During a median follow-up of 2.0 years (interquartile range, 1.0–3.0), 40 children had a recurrent AIS, and none had a hemorrhagic stroke. The cumulative stroke recurrence rate was 6.8% (95% confidence interval, 4.6%–10%) at 1 month and 12% (8.5%–15%) at 1 year. The sole predictor of recurrence was the presence of an arteriopathy, which increased the risk of recurrence 5-fold when compared with an idiopathic AIS (hazard ratio, 5.0; 95% confidence interval, 1.8–14). The 1-year recurrence rate was 32% (95% confidence interval, 18%–51%) for moyamoya, 25% (12%–48%) for transient cerebral arteriopathy, and 19% (8.5%–40%) for arterial dissection. Conclusions— Children with AIS, particularly those with arteriopathy, remain at high risk for recurrent AIS despite increased utilization of antithrombotic agents. Therapies directed at the arteriopathies themselves are needed.

Acute Silent Cerebral Ischemic Events in Children With Sickle Cell Anemia

BACKGROUND Irregular, sporadic episodes of ischemic brain injury are known to occur in sickle cell anemia (SCA), resulting in overt stroke and silent cerebral infarction. Ongoing ischemia in other organs is common in SCA but has never been documented in the brain. OBJECTIVE To test the hypothesis that acute silent cerebral ischemic events (ASCIEs) are frequent and potentially transient. DESIGN Cross-sectional and cohort study of children with SCA screened by magnetic resonance imaging (MRI) of the brain for a randomized clinical trial. SETTING Clinical trial setting in tertiary care centers. PATIENTS Asymptomatic children with SCA without known stroke, neurologic injury, or epilepsy not receiving treatment with transfusions or hydroxyurea. MAIN OUTCOME MEASURE Incidence of ASCIEs calculated using single diffusion-weighted MRI scans (acute ischemic events that occurred within 10 days of the MRI). RESULTS Acute silent cerebral ischemic events were detected on 1.3% of MRIs (10 of 771) in 652 children (mean age, 10.0 years), with an incidence of 47.3 events per 100 patient-years (95% CI, 22.7-87.2). Two of 10 children with ASCIEs had follow-up MRIs of the brain; only 1 had silent cerebral infarction in the same location as the previously detected ASCIE. CONCLUSIONS Children with SCA experience ongoing (chronic, intermittent) cerebral ischemia, sometimes reversible, far more frequently than previously recognized. The brain in SCA is at constant threat of ischemia.

International Paediatric Stroke Study: stroke associated with cardiac disorders.

Background and hypothesis The aetiologies of arterial ischaemic stroke in children are diverse and often multifactorial. A large proportion occurs in children with cardiac disorders. We hypothesized that the clinical and radiographic features of children with arterial ischaemic stroke attributed to cardiac disorders would differ from those with other causes. Methods Using the large population collected in the prospective International Paediatric Stroke Study, we analysed the characteristics, clinical presentations, imaging findings, and early outcomes of children with and without cardiac disorders. Results Aetiological data were available for 667 children with arterial ischaemic stroke (ages 29 days to 19 years). Cardiac disorders were indentified in 204/667 (30·6%), congenital defects in 121/204 (59·3%), acquired in 40/204 (19·6%), and isolated patent foramen ovale in 31/204 (15·2%). Compared to other children with stroke, those with cardiac disorders were younger (median age 3·1 vs. 6·5 years; P < 0·001) and less likely to present with headache (25·6% vs. 44·6%; P < 0·001), but were similar in terms of gender and presentation with focal deficits, seizures, or recent infection. Analysis of imaging data identified significant differences (P = 0·005) in the vascular distribution (anterior vs. posterior circulation or both) between groups. Bilateral strokes and haemorrhagic conversion were more prevalent in the cardiac disorders group. Conclusions Cardiac disorders were identified in almost one-third of children with arterial ischaemic stroke. They had similar clinical presentations to those without cardiac disorders but differed in age and headache prevalence. Children with cardiac disorders more frequently had a ‘cardioembolic stroke pattern’ with a higher prevalence of bilateral strokes in both the anterior and posterior circulations, and a greater tendency to haemorrhagic transformation.

Herpesvirus Infections and Childhood Arterial Ischemic Stroke Results of the VIPS Study

Background— Epidemiological studies demonstrate that childhood infections, including varicella zoster virus, are associated with an increased risk of arterial ischemic stroke (AIS). Other herpesviruses have been linked to childhood AIS in case reports. We sought to determine whether herpesvirus infections, which are potentially treatable, increase the risk of childhood AIS. Methods and Results— We enrolled 326 centrally confirmed cases of AIS and 115 stroke-free controls with trauma (29 days to 18 years of age) with acute blood samples (⩽3 weeks after stroke/trauma); cases had convalescent samples (7–28 days later) when feasible. Samples were tested by commercial enzyme-linked immunosorbent assay kits for immunoglobulin M/immunoglobulin G antibodies to herpes simplex virus 1 and 2, cytomegalovirus, Epstein-Barr virus, and varicella zoster virus. An algorithm developed a priori classified serological evidence of past and acute herpesvirus infection as dichotomous variables. The median (quartiles) age was 7.7 (3.1–14.3) years for cases and 10.7 (6.9–13.2) years for controls (P=0.03). Serological evidence of past infection did not differ between cases and controls. However, serological evidence of acute herpesvirus infection doubled the odds of childhood AIS, even after adjusting for age, race, and socioeconomic status (odds ratio, 2.2; 95% confidence interval, 1.2–4.0; P=0.007). Among 187 cases with acute and convalescent blood samples, 85 (45%) showed evidence of acute herpesvirus infection; herpes simplex virus 1 was found most often. Most infections were asymptomatic. Conclusions— Herpesviruses may act as a trigger for childhood AIS, even if the infection is subclinical. Antivirals like acyclovir might have a role in the prevention of recurrent stroke if further studies confirm a causal relationship.

Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene

Infantile-onset X-linked spinal muscular atrophy (SMAX2) is a rare lethal disorder linked to mutations in the UBA1 (previously UBE1) gene, encoding ubiquitin-activating enzyme 1 that has an important role in the ubiquitin-proteasome pathway. Published pathological reports are scarce. Here we report a male infant who presented from birth with predominantly truncal hypotonia following an antenatal history of reduced fetal movements. He had a myopathic face, profound weakness, multiple contractures and areflexia. Creatine kinase was moderately raised. Brain MRI showed non-specific symmetrical periventricular white matter changes. Neurophysiology revealed evidence of motor and sensory involvement and muscle biopsy showed marked inflammatory changes with subtle features suggestive of acute denervation. UBA1 sequencing revealed a novel hemizygous missense mutation (c.1670A>T; p.Glu557Val). He died from progressive respiratory failure at 4 months. On post mortem assessment, in addition to severe ventral motor neuron pathology, there was widespread involvement of the sensory system, as well as developmental and degenerative cerebellar abnormalities. In contrast to typical SMN1-associated SMA, the thalamus was unaffected. These findings indicate that SMAX2 is more accurately classified as a motor sensory neuronopathy rather than a pure anterior horn cell disorder. Ubiquitin-proteasome pathway defects may not only cause neurodegeneration but also affect normal neuronal development.

N-methyl-D-aspartate receptor antibody-associated movement disorder without encephalopathy

N‐methyl‐D‐aspartate receptor (NMDAR) antibody encephalitis is a well‐recognized clinico‐immunological syndrome that presents with a movement disorder, cognitive decline, psychiatric symptoms, and epileptic seizures. A pure monosymptomatic presentation is rare; however, some patients present predominantly with a movement disorder in the absence of encephalopathy. Here, we describe three paediatric patients with an NMDAR antibody‐mediated movement disorder: a 5‐year‐old female with acute onset hemichorea, a 10‐year‐old female with generalized chorea, and a 12‐year‐old male with abdominal myoclonus. These patients did not develop the characteristic encephalopathy syndrome seen in NMDAR encephalitis, but all three had other associated subtle cognitive deficits. The patients demonstrated good responses to immunotherapy.

Intellectual ability and executive function in pediatric moyamoya vasculopathy

Aim  Moyamoya vasculopathy is characterized by progressive stenosis of the major arteries of the Circle of Willis, resulting in compromised cerebral blood flow and increased risk of stroke. The objectives of the current study were to examine intellectual and executive functioning of children with moyamoya and to evaluate the impact of moyamoya type, stroke (clinical or silent), vasculopathy laterality, and disease duration on neurocognitive abilities.

Generalized arterial calcification of infancy: Phenotypic spectrum among three siblings including one case without obvious arterial calcifications†‡

Generalized arterial calcification of infancy (GACI) (OMIM no. 208000) is characterized by calcification of the major arteries and soft tissues and associated with mutations in the ENPP1 gene. Most affected patients die within the first 6 months of life although prolonged survival is increasingly recognized. We report on three siblings with GACI and striking phenotypic variability. Two siblings (including the sibling survivor) were compound heterozygotes for mutations in exon 7 (c.783C>G (p.Y261X)) and exon 8 (c. 878_879delAA (p.K293fsX5)) of the ENPP1 gene confirming the diagnosis of GACI. The sibling survivor did not have calcification on X‐ray studies or evidence of hypophosphatemic rickets. GACI may be under recognized and we emphasize consideration of this condition in patients with multiple arterial stenosis even in the absence of radiographic calcification. This adds to the expanding phenotype of GACI and supports a potential role for modifying genes.