Safety and efficacy of nusinersen in spinal muscular atrophy: The EMBRACE study.

INTRODUCTION: The EMBRACE study (Clinical Trials No. NCT02462759) evaluated nusinersen in infants/children with infantile- or later-onset spinal muscular atrophy (SMA) who were ineligible for the ENDEAR and CHERISH studies. METHODS: Participants were randomized to intrathecal nusinersen (12-mg scaled equivalent dose; n = 14) or sham procedure (n = 7) in part 1 (~14 months) and subsequently received open-label nusinersen for ~24 months in part 2 of the study. RESULTS: Part 1 was stopped early after the demonstration of motor function benefit with nusinersen in ENDEAR. There were no nusinersen-related adverse events (AEs) and no study discontinuations due to nusinersen-related AEs. The most common AEs included pyrexia, cough, pneumonia, and upper respiratory tract infections. Motor milestone responder rates were higher in those receiving nusinersen at last available assessment (93%) than in those receiving sham procedure in part 1 (29%) or transitioned from sham to nusinersen in part 2 (83%). This functional improvement was observed despite the small sample size and shortened part 1 trial duration that undermined the power of the study to demonstrate such treatment effects at a significant level. DISCUSSION: Nusinersen demonstrated a favorable long-term benefit-risk profile in this broad population of individuals with infantile- or later-onset SMA.

De novo mutations in the motor domain of KIF1A cause cognitive impairment, spastic paraparesis, axonal neuropathy, and cerebellar atrophy.

KIF1A is a neuron-specific motor protein that plays important roles in cargo transport along neurites. Recessive mutations in KIF1A were previously described in families with spastic paraparesis or sensory and autonomic neuropathy type-2. Here, we report 11 heterozygous de novo missense mutations (p.S58L, p.T99M, p.G102D, p.V144F, p.R167C, p.A202P, p.S215R, p.R216P, p.L249Q, p.E253K, and p.R316W) in KIF1A in 14 individuals, including two monozygotic twins. Two mutations (p.T99M and p.E253K) were recurrent, each being found in unrelated cases. All these de novo mutations are located in the motor domain (MD) of KIF1A. Structural modeling revealed that they alter conserved residues that are critical for the structure and function of the MD. Transfection studies suggested that at least five of these mutations affect the transport of the MD along axons. Individuals with de novo mutations in KIF1A display a phenotype characterized by cognitive impairment and variable presence of cerebellar atrophy, spastic paraparesis, optic nerve atrophy, peripheral neuropathy, and epilepsy. Our findings thus indicate that de novo missense mutations in the MD of KIF1A cause a phenotype that overlaps with, while being more severe, than that associated with recessive mutations in the same gene.

Truncating CLCN1 mutations in myotonia congenita: variable patterns of inheritance.

INTRODUCTION: Myotonia congenita due to protein truncating CLCN1 mutations is associated with variable patterns of inheritance. METHODS: Three family kindreds are described, all of whom possess protein truncating mutations (Y33X, fs503X, R894X). One lineage also has coexistent R894X, A313T, and A320V mutations. RESULTS: The Y33X mutation kinship has autosomal recessive inheritance and a severe phenotype when homozygous. The fs503X family has autosomal dominant inheritance and a moderate-to-severe phenotype. The A313T mutation kindred also has autosomal dominant inheritance but expresses a mild phenotype, except for the more severely affected compound heterozygotes. CONCLUSIONS: Early truncating mutations precluding dimerization are expected to be autosomal recessive and express a severe phenotype, while later mutations may be variable. The pedigrees presented here demonstrate that intrafamilial phenotypic variability may result from a dosage effect of an additional mutation, not necessarily variable expressivity. Mutations that have unexpected patterns of inheritance may represent allelic variability.

The recurrent deep intronic pseudoexon-inducing variant COL6A1 c.930+189C>T results in a consistently severe phenotype of COL6-related dystrophy: Towards clinical trial readiness for splice-modulating therapy.

Collagen VI-related dystrophies (COL6-RDs) manifest with a spectrum of clinical phenotypes, ranging from Ullrich congenital muscular dystrophy (UCMD), presenting with prominent congenital symptoms and characterised by progressive muscle weakness, joint contractures and respiratory insufficiency, to Bethlem muscular dystrophy, with milder symptoms typically recognised later and at times resembling a limb girdle muscular dystrophy, and intermediate phenotypes falling between UCMD and Bethlem muscular dystrophy. Despite clinical and immunohistochemical features highly suggestive of COL6-RD, some patients had remained without an identified causative variant in COL6A1, COL6A2 or COL6A3. With combined muscle RNA-sequencing and whole-genome sequencing we uncovered a recurrent, de novo deep intronic variant in intron 11 of COL6A1 (c.930+189C>T) that leads to a dominantly acting in-frame pseudoexon insertion. We subsequently identified and have characterised an international cohort of forty-four patients with this COL6A1 intron 11 causative variant, one of the most common recurrent causative variants in the collagen VI genes. Patients manifest a consistently severe phenotype characterised by a paucity of early symptoms followed by an accelerated progression to a severe form of UCMD, except for one patient with somatic mosaicism for this COL6A1 intron 11 variant who manifests a milder phenotype consistent with Bethlem muscular dystrophy. Characterisation of this individual provides a robust validation for the development of our pseudoexon skipping therapy. We have previously shown that splice-modulating antisense oligomers applied in vitro effectively decreased the abundance of the mutant pseudoexon-containing COL6A1 transcripts to levels comparable to the in vivo scenario of the somatic mosaicism shown here, indicating that this therapeutic approach carries significant translational promise for ameliorating the severe form of UCMD caused by this common recurrent COL6A1 causative variant to a Bethlem muscular dystrophy phenotype.

Isolated lower brachial plexus (Klumpke) palsy with compound arm presentation: case report.

Klumpke palsy has yet to be clearly documented in the newborn, because previous reports lack any description of the obstetrical history, clinical progression, or outcome. Based on a high incidence of breach presentation in the few clinical series that report Klumpke palsy, hyperabduction with arm overhead during delivery has been the presumed mechanism. We report a child with isolated lower brachial plexus palsy and Horner syndrome who presented at birth with a vertex compound arm presentation. Recognition of this condition and details of the clinical progression and outcome are important, because guidelines for management are currently not available.

Severe case and literature review of primary erythromelalgia: novel SCN9A gene mutation.

Erythromelalgia is a rare clinical syndrome characterized by intermittent heat, redness, swelling and pain more commonly affecting the lower extremities. Symptoms are mostly aggravated by warmth and are eased by a cold temperature. In some cases, symptoms can be very severe and disabling. Erythromelalgia can be classified as either familial or sporadic, with the familial form inherited in an autosomal dominant manner. Recently, there has been a lot of progress in studying Na(v)1.7 sodium channels (expressed mostly in the sympathetic and nociceptive small-diameter sensory neurons of the dorsal root ganglion) and different mutations affecting the encoding SCN9A gene that leads to channelopathies responsible for some disorders, including primary erythromelalgia. We present a severe case of progressive primary erythromelalgia caused by a new de novo heterozygous missense mutation (c.2623C>G) of the SCN9A gene which substitutes glutamine 875 by glutamic acid (p.Q875E). To our knowledge, this mutation has not been previously reported in the literature. We also provided a short literature review about erythromelalgia and Na(v) sodium channelopathies.

Spinocerebellar ataxia type 29 due to mutations in ITPR1: a case series and review of this emerging congenital ataxia.

BACKGROUND: Spinocerebellar ataxia type 29 (SCA29) is an autosomal dominant, non-progressive cerebellar ataxia characterized by infantile-onset hypotonia, gross motor delay and cognitive impairment. Affected individuals exhibit cerebellar dysfunction and often have cerebellar atrophy on neuroimaging. Recently, missense mutations in ITPR1 were determined to be responsible. RESULTS: Clinical information on 21 individuals from 15 unrelated families with ITPR1 mutations was retrospectively collected using standardized questionnaires, including 11 previously unreported singletons and 2 new patients from a previously reported family. We describe the genetic, clinical and neuroimaging features of these patients to further characterize the clinical features of this rare condition and assess for any genotype-phenotype correlation for this disorder. Our cohort consisted of 9 males and 12 females, with ages ranging from 28 months to 49 years. Disease course was non-progressive with infantile-onset hypotonia and delays in motor and speech development. Gait ataxia was present in all individuals and 10 (48%) were not ambulating independently between the ages of 3-12 years of age. Mild-to-moderate cognitive impairment was present in 17 individuals (85%). Cerebellar atrophy developed after initial symptom presentation in 13 individuals (72%) and was not associated with disease progression or worsening functional impairment. We identified 12 different mutations including 6 novel mutations; 10 mutations were missense (with 4 present in >1 individual), 1 a splice site mutation leading to an in-frame insertion and 1 an in-frame deletion. No specific genotype-phenotype correlations were observed within our cohort. CONCLUSIONS: Our findings document significant clinical heterogeneity between individuals with SCA29 in a large cohort of molecularly confirmed cases. Based on the retrospective observed clinical features and disease course, we provide recommendations for management. Further research into the natural history of SCA29 through prospective studies is an important next step in better understanding the condition.

Unilateral myokymia of the tongue after radiation therapy for cervical nodal melanoma.

Hypoglossal neuropathy with associated myokymia as a delayed effect of radiation is a rare occurrence, presumably due to the relative resistance of cranial nerves to injury from irradiation. The authors describe the first case of myokymia of the unilateral tongue with myokymic discharges on needle electromyography after hypofractionated radiation therapy for an extracranial melanoma of the neck. The earlier onset of myokymia than previous cases may represent more direct radiation exposure due to radiation site or the higher radiation dosage administered for treatment of melanomas.

Comparison of accidental and nonaccidental traumatic head injury in children on noncontrast computed tomography.

OBJECTIVE: Mixed-density convexity subdural hematoma and interhemispheric subdural hematoma suggest nonaccidental head injury. The purpose of this retrospective observational study is to investigate subdural hematoma on noncontrast computed tomography in infants with nonaccidental head injury and to compare these findings in infants with accidental head trauma for whom the date of injury was known. PATIENTS AND METHODS: Two blinded, independent observers retrospectively reviewed computed tomography scans with subdural hematoma performed on the day of presentation on 9 infant victims of nonaccidental head injury (mean age: 6.8 months; range: 1-25 months) and on 38 infants (mean age: 4.8 months; range: newborn to 34 months) with accidental head trauma (birth-related: 19; short fall: 17; motor vehicle accident: 2). RESULTS: Homogeneous hyperdense subdural hematoma was significantly more common in children with accidental head trauma (28 of 38 [74%]; nonaccidental head trauma: 3 of 9 [33%]), whereas mixed-density subdural hematoma was significantly more common in cases of nonaccidental head injury (6 of 9 [67%]; accidental head trauma: 7 of 38 [18%]). Twenty-two (79%) subdural hematomas were homogeneously hyperdense on noncontrast computed tomography performed within two days of accidental head trauma, one (4%) was homogeneous and isodense compared to brain tissue, one (4%) was homogeneous and hypodense, and four (14%) were mixed-density. There was no statistically significant difference in the proportion of interhemispheric subdural hematoma, epidural hematoma, calvarial fracture, brain contusion, or subarachnoid hemorrhage. CONCLUSIONS: Homogeneous hyperdense subdural hematoma is more frequent in cases of accidental head trauma; mixed-density subdural hematoma is more frequent in cases of nonaccidental head injury but may be observed within 48 hours of accidental head trauma. Interhemispheric subdural hematoma is not specific for inflicted head injury.

Inhibitory network properties shaping the light evoked responses of cat alpha retinal ganglion cells.

Cat retinal ganglion cells of the Y (or alpha) type respond to luminance changes opposite those preferred by their receptive-field centers with a transient hyperpolarization. Here, we examine the spatial organization and synaptic basis of this light response by means of whole-cell current-clamp recordings made in vitro. The hyperpolarization was largest when stimulus spots approximated the size of the receptive-field center, and diminished substantially for larger spots. The hyperpolarization was largely abolished by bath application of strychnine, a blocker of glycinergic inhibition. Picrotoxin, an antagonist of ionotropic GABA receptors, greatly reduced the attenuation of the hyperpolarizing response for large spots. The data are consistent with a model in which (1) the hyperpolarization reflects inhibition by glycinergic amacrine cells of bipolar terminals presynaptic to the alpha cells, and perhaps direct inhibition of the alpha cell as well; and (2) the attenuation of the hyperpolarization by large spots reflects surround inhibition of the glycinergic amacrine by GABAergic amacrine cells. This circuitry may moderate nonlinearities in the alpha-cell light response and could account for some excitatory and inhibitory influences on alpha cells known to arise from outside the classical receptive field.

Intrinsic physiological properties of cat retinal ganglion cells.

Retinal ganglion cells (RGCs) are the output neurons of the retina, sending their signals via the optic nerve to many different targets in the thalamus and brainstem. These cells are divisible into more than a dozen types, differing in receptive field properties and morphology. Light responses of individual RGCs are in large part determined by the exact nature of the retinal synaptic network in which they participate. Synaptic inputs, however, are greatly influenced by the intrinsic membrane properties of each cell. While it has been demonstrated clearly that RGCs vary in their intrinsic properties, it remains unclear whether this variation is systematically related to RGC type. To learn whether membrane properties contribute to the functional differentiation of RGC types, we made whole-cell current clamp recordings of RGC responses to injected current of identified cat RGCs. The data collected demonstrated that RGC types clearly differed from one another in their intrinsic properties. One of the most striking differences we observed was that individual cell types had membrane time constants that varied widely from approximately 4 ms (alpha cells) to more than 80 ms (zeta cells). Perhaps not surprisingly, we also observed that RGCs varied greatly in their maximum spike frequencies (kappa cells 48 Hz-alpha cells 262 Hz) and sustained spike frequencies (kappa cells 23 Hz-alpha cells 67 Hz). Interestingly, however, most RGC types exhibited similar amounts of spike frequency adaptation. Finally, RGC types also differed in their responses to injection of hyperpolarizing current. Most cell types exhibited anomalous rectification in response to sufficiently strong hyperpolarization, although alpha and beta RGCs showed only minimal, if any, rectification under similar conditions. The differences we observed in RGC intrinsic properties were striking and robust. Such differences are certain to affect how each type responds to synaptic input and may help tune each cell type appropriately for their individual roles in visual processing.