P. Munot

Muscle Magnetic Resonance Imaging in Congenital Myopathies Due to Ryanodine Receptor Type 1 Gene Mutations

OBJECTIVES To establish the consistency of the previously reported pattern of muscle involvement in a large cohort of patients with molecularly defined ryanodine receptor type 1 (RYR1)-related myopathies, to identify possible additional patterns, and to compare magnetic resonance imaging (MRI) findings with clinical and genetic findings. DESIGN Blinded analysis of muscle MRI patterns of patients with congenital myopathies with dominant or recessive RYR1 mutations and control patients without RYR1 mutations. We compared MRI findings with the previously reported pattern of muscle involvement. SETTING Data from 3 tertiary referral centers. PATIENTS Thirty-seven patients with dominant or recessive RYR1 mutations and 23 controls with other myopathies. MAIN OUTCOME MEASURES Each MRI was classified as typical if it was identical to the reported pattern, consistent if it was similar to the reported one but with some additional features, or different. Images with no or few changes were classified as uninformative. RESULTS Twenty-one of 37 patients with RYR1 mutations had a typical pattern; 13 had a consistent pattern. Two patients had uninformative MRIs and only 1 had a different pattern. Compared with patients with dominant mutations, patients with recessive mutations and ophthalmoparesis had a more diffuse pattern, classified as consistent in 6 of 8. In contrast, 10 of 11 with recessive mutations but without ophthalmoparesis had a typical pattern. All MRIs of 23 control patients were classified as different. CONCLUSIONS Our results suggest that muscle MRI is a powerful predictor of RYR1 involvement in patients with a congenital myopathy, especially if they carry a dominant mutation or recessive mutations without ophthalmoparesis.

Congenital fibre type disproportion associated with mutations in the tropomyosin 3 (TPM3) gene mimicking congenital myasthenia

Congenital myopathy with fibre type disproportion (CFTD) has been associated with mutations in ACTA1, SEPN1, RYR1 and TPM3 genes. We report the clinico-pathological and electrophysiological features of 2 unrelated cases with heterozygous TPM3 mutation. Case 1 is a 19-year-old lady who presented with motor delay in infancy, respiratory failure in early teens requiring non-invasive ventilation despite being ambulant, ptosis, axial more than proximal weakness and scoliosis. Case 2 is a 7-year-old boy with hypotonia, feeding difficulties, motor delay and scoliosis, also requiring non-invasive ventilation while ambulant. Muscle biopsies in both cases showed fibre type disproportion. Muscle MRI (Case 1) showed mild uniformly increased interstitial tissue in and around the muscles. Sequencing of TPM3 in case 1 revealed a previously described heterozygous c.503G > A(pArg168His) missense variant in exon 5 and a novel heterozygous missense mutation c.521A > C(pGlu174Ala), also in exon 5, in case 2. A mild abnormality in the single fibre EMG was documented on electrophysiology in both cases. These cases highlight the neuromuscular transmission defect in CFTD secondary to TPM3 mutations.

Paediatric stroke: genetic insights into disease mechanisms and treatment targets.

In children, stroke is as common as brain tumour and causes substantial mortality and long-term morbidity, with recurrence in up to 20%. There are three sets of international clinical guidelines relating to childhood stroke; however, acute and preventive treatment recommendations are based on interventions effective in adults, rather than data regarding efficacy in children. A wide spectrum of risk factors underlies childhood stroke, and these risk factors vary from those encountered in adults. Specific disease mechanisms implicated in childhood arterial ischaemic stroke have received little attention, but an increased understanding of disease pathogenesis could lead to novel targeted treatment approaches. Here, we consider insights into the pathogenesis of childhood arterial ischaemic stroke and cerebral arteriopathy, provided by current knowledge of Mendelian diseases that are associated with an increased risk of these conditions. We give particular attention to aspects of vascular development, homoeostasis, and response to environmental effects. Our analysis highlights a potential role for interventions already licensed for pharmaceutical use, as well as new therapeutic targets and avenues for further research.

Severe iron deficiency anaemia and ischaemic stroke in children

Iron deficiency anaemia (IDA) has a peak prevalence of 4–8% in children aged 1–3 years of age and is known to be associated with developmental delay, lethargy, irritability and cognitive problems. Rarely, IDA has also been reported as a risk factor for stroke in otherwise healthy children. We report a series of four young children aged 14 months to 48 months with significant IDA. Three children had venous sinus thrombosis and one had arterial ischaemic stroke, without other risk factors. We discuss the potential underlying mechanisms and review the relevant literature. This report further consolidates the evidence for a strong association between IDA and childhood stroke and highlights an easily treatable (and preventable) risk factor.

Dihydropyridine receptor (DHPR, CACNA1S) congenital myopathy

Muscle contraction upon nerve stimulation relies on excitation–contraction coupling (ECC) to promote the rapid and generalized release of calcium within myofibers. In skeletal muscle, ECC is performed by the direct coupling of a voltage-gated L-type Ca2+ channel (dihydropyridine receptor; DHPR) located on the T-tubule with a Ca2+ release channel (ryanodine receptor; RYR1) on the sarcoplasmic reticulum (SR) component of the triad. Here, we characterize a novel class of congenital myopathy at the morphological, molecular, and functional levels. We describe a cohort of 11 patients from 7 families presenting with perinatal hypotonia, severe axial and generalized weakness. Ophthalmoplegia is present in four patients. The analysis of muscle biopsies demonstrated a characteristic intermyofibrillar network due to SR dilatation, internal nuclei, and areas of myofibrillar disorganization in some samples. Exome sequencing revealed ten recessive or dominant mutations in CACNA1S (Cav1.1), the pore-forming subunit of DHPR in skeletal muscle. Both recessive and dominant mutations correlated with a consistent phenotype, a decrease in protein level, and with a major impairment of Ca2+ release induced by depolarization in cultured myotubes. While dominant CACNA1S mutations were previously linked to malignant hyperthermia susceptibility or hypokalemic periodic paralysis, our findings strengthen the importance of DHPR for perinatal muscle function in human. These data also highlight CACNA1S and ECC as therapeutic targets for the development of treatments that may be facilitated by the previous knowledge accumulated on DHPR.

Characteristics of Childhood Arterial Ischemic Stroke With Normal MR Angiography

Background and Purpose— The purposes of this study were to describe clinical and radiological characteristics of children with arterial ischemic stroke and normal MRA to compare them with children with arterial ischemic stroke and abnormal MRA. Methods— We conducted a retrospective review of clinical records and imaging. Results— Forty children with arterial ischemic stroke and normal MRA were identified (24 male; median age, 55 months). MRA had been acquired <24 hours of symptom onset in 4, at 24 to 48 hours in 10, 48 to 96 hours in 10, 4 to 7 days in 10, and >1 week in 6 children (median, 4 days). Ten of 40 had prior diagnoses (5 cardiac, 5 malignancies). Other risk factors were identified in 30 (1 in 17 and >1 in 13; prothrombotic abnormalities in 14, prior Varicella in 7, anemia in 7, minor trauma in 4). Infarction was confined to the lenticulostriate branches of the middle cerebral artery in 21 of 40. Two patients had further clinical events, both with new infarcts; 28 patients were reimaged and MRA remained normal in all. Although similar in terms of age and gender to those with abnormal MRA, children with normal MRA were significantly more likely to have at least 1 RF (P=0.012). Those with abnormal MRA were significantly more likely to have multiple territory infarcts (P<0.001), but lesion topography was otherwise not predictive of abnormal MRA (P=0.45). Abnormal MRA was significantly associated with clinical recurrence (P<0.001). Conclusions— Children with arterial ischemic stroke and normal MRA are not a distinct demographic group but are more likely to have single-territory lesions and have nonvascular risk factors. The stroke mechanism in children with normal MRA remains unclear.

The neuropathological consequences of CDKL5 mutation

A wide range of mutations in the X-linked gene cyclindependent kinase-like 5 (CDKL5), causing either frameshifts or interfering with the splice sites, have been described in children of both sexes with early-onset epileptic encephalopathy, infantile spasms and a Rett syndromelike phenotype [1–4]. In the majority of mutation carriers, brain MRI is normal but non-specific abnormalities including cerebral atrophy and reduced white matter bulk or myelination have been reported [2,5–16]. The neuropathological consequences of CDKL5 mutations have not been previously described. We present the neuropathology of a child with infantile spasms and a Rett-like syndrome who carried a de novo, novel CDKL5 mutation and who suffered a sudden unexpected death at the age of 5 years. We found malformations and striking ongoing degeneration in the cerebellum. It is likely that some of these features are attributable to the gene mutation. Following an uneventful pregnancy, a girl was born at 35 weeks’ gestation to non-consanguineous parents. Her birth weight was 2.47 kg.The child’s mother and maternal grandfather have fatigable right ptosis. At the age of 11 weeks, she presented with focal clonic seizures, which subsequently became generalized. EEG did not show any epileptiform activity. At 18 months, her seizures evolved in to infantile spasms, which were treated with steroids and vigabatrin. EEG showed multifocal polymorphic spike waves, suggestive of epileptic encephalopathy. At 2 years of age her infantile spasms resolved and she developed clusters of tonic seizures that were refractory to several antiepileptic drugs. EEG showed marked abnormality with frequent central and fronto-central epileptiform activity. Her development was delayed: she sat at 16 months and achieved supported standing at 20 months. After a period of poor seizure control at 20 months she significantly regressed and stopped sitting and talking. These skills were not recovered. She had been hyperkinetic since infancy with mixed dystonic and choreoathetoid movements and occasional opisthotonus. Her vision was severely restricted and she was unable to fix or follow. It was not possible to test her hearing. She had a poor swallow and had frequent aspirations. There were no dysmorphic features but her head circumference was >2 SD below the mean. Brain MRI between the ages of 2 and 4 years demonstrated progressive cerebral and cerebellar atrophy without any focal lesions. Brainstem-evoked responses were normal but her visual evoked potentials demonstrated significant impairment of visual cortical function. Extensive metabolic investigations and respiratory chain studies were normal. A skeletal muscle biopsy showed a mild excess of lipid but no diagnostic features. Mutation analyses for SCN1A, Angelman syndrome (UBE3A) and Rett syndrome (MECP2) were negative. Array-CGH was negative and a karyotype normal. Analysis of CDKL5 showed a novel heterozygous mutation c.2277-2A>G which is predicted to destroy the splice acceptor site of exon 16. At the age of 5 years, she was found dead in bed in the early hours of the morning, having been well the previous day. A careful review of her history showed that at no point had she received phenytoin. A detailed post mortem examination was undertaken, according to a standard protocol, which involved histological examination of all major organ systems, detailed microbiology and toxicology. The only significant abnormalities were in the central nervous system. The fixed brain weighed 1010 g and the structures of the posterior fossa weighed 118 g (11.7% of total brain weight). The occipital poles were flattened, giving a brachycephalic appearance (Figure 1). On the base of the brain, the temporal poles were drawn inwards and directed towards the midline. From the exterior, both superior temporal gyri appeared small but on coronal section they were of normal size but deeply buried. The lateral and third ventricles were enlarged throughout. The cerebellar vermis and hemispheres were macroscopically normal. Microscopically, the main findings were in the vermis and cerebellum where there were a small number of short

Skeletal Muscle Channelopathies: Rare Disorders with Common Pediatric Symptoms

Objective To ascertain the presenting symptoms of children with skeletal muscle channelopathies to promote early diagnosis and treatment. Study design Retrospective case review of 38 children with a skeletal muscle channelopathy attending the specialist pediatric neuromuscular service at Great Ormond Street Hospital over a 15‐year period. Results Gait disorder and leg cramps are a frequent presentation of myotonic disorders (19 of 29). Strabismus or extraocular myotonia (9 of 19) and respiratory and/or bulbar symptoms (11 of 19) are common among those with sodium channelopathy. Neonatal hypotonia was observed in periodic paralysis. Scoliosis and/or contractures were demonstrated in 6 of 38 children. School attendance or ability to engage fully in all activities was often limited (25 of 38). Conclusions Children with skeletal muscle channelopathies frequently display symptoms that are uncommon in adult disease. Any child presenting with abnormal gait, leg cramps, or strabismus, especially if intermittent, should prompt examination for myotonia. Those with sodium channel disease should be monitored for respiratory or bulbar complications. Neonatal hypotonia can herald periodic paralysis. Early diagnosis is essential for children to reach their full educational potential.

Clinical spectrum, treatment and outcome of children with suspected diagnosis of chronic inflammatory demyelinating polyradiculoneuropathy

Highlights • The diagnosis of CIDP can be challenging.• In our cohort 52% were diagnosed as CIDP on re-evaluation.• Cranial nerve abnormality is rare and may be only presenting symptom.• Children require long-term follow up as the course may be protracted.• With early treatment majority have good recovery and maintain ambulation.

STAC3 variants cause a congenital myopathy with distinctive dysmorphic features and malignant hyperthermia susceptibility

SH3 and cysteine‐rich domain‐containing protein 3 (STAC3) is an essential component of the skeletal muscle excitation–contraction coupling (ECC) machinery, though its role and function are not yet completely understood.