Transitioning From Nusinersen to Risdiplam for Spinal Muscular Atrophy in Clinical Practice: A Single-Center Experience.

Background: Nusinersen and risdiplam are U.S. Food and Drug Administration (FDA)-approved treatments for spinal muscular atrophy (SMA).

Continued safety and long-term effectiveness of onasemnogene abeparvovec in Ohio.

5q spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disease caused by absence of the SMN1 gene with three FDA approved genetic therapies which significantly improve outcomes. The AAV9 mediated gene replacement therapy, onasemnogene abeparvovec, has the greatest potential for side effects. Here we report the safety and outcomes from 46 children treated with onasemnogene abeparvovec in the state of Ohio between December 2018 and January 2023.

Pathogenic missense variants altering codon 336 of GARS1 lead to divergent dominant phenotypes.

Heterozygosity for missense variants and small in-frame deletions in GARS1 has been reported in patients with a range of genetic neuropathies including Charcot-Marie-Tooth disease type 2D (CMT2D), distal hereditary motor neuropathy type V (dHMN-V), and infantile spinal muscular atrophy (iSMA). We identified two unrelated patients who are each heterozygous for a previously unreported missense variant modifying amino-acid position 336 in the catalytic domain of GARS1. One patient was a 20-year-old woman with iSMA, and the second was a 41-year-old man with CMT2D.

Validity and Reliability of the Neuromuscular Gross Motor Outcome.

Background: Approved treatments in spinal muscular atrophy (SMA) have resulted in unprecedented gains for many individuals. Use of available outcomes, typically developed for a specific type of SMA, do not cover the range of progression, often resulting in a battery of functional testing being completed at visits. Our objective was to validate the Neuromuscular Gross Motor Outcome (GRO) as a tool to quantify function in SMA across the span of abilities.

Natural History of Steroid-Treated Young Boys With Duchenne Muscular Dystrophy Using the NSAA, 100m, and Timed Functional Tests.

Introduction: Clinical trials targeting younger cohorts of boys with Duchenne muscular dystrophy are necessary as earlier intervention may maximize treatment effect. Boys with Duchenne muscular dystrophy often have gross motor delays very early in life, and although they gain skills, they are on a lower trajectory than typical peers. Quantifying the natural rate of motor maturation in Duchenne muscular dystrophy from an early age permits identification of deviations from the expected trajectory related to treatment effects.

ACTIVE (Ability Captured Through Interactive Video Evaluation) workspace volume video game to quantify meaningful change in spinal muscular atrophy.

Aim: To evaluate the utility of Ability Captured Through Interactive Video Evaluation (ACTIVE) scaled scores to quantify meaningful change in individuals with spinal muscular atrophy (SMA) types 2 or 3 due to disease progression or treatment.

Method: ACTIVE is a custom-designed video game that measures workspace volume (WSV). Participants included 62 individuals with SMA (mean age [SD] 10y 9mo [5y], range 2y 9mo-24y) and 362 frequency-matched controls (mean age [SD] 10y 9mo [3y 6mo], range 3y 2mo-24y 9mo).

Diagnostic Utility of Whole Exome Sequencing in the Neuromuscular Clinic.

Next-generation sequencing is a powerful diagnostic tool, yet it has proven inadequate to establish a diagnosis in all cases of congenital hypotonia or childhood onset weakness. We sought to describe the impact of whole exome sequencing (WES), which has only recently become widely available clinically, on molecular diagnosis in the Nationwide Children's Hospital Neuromuscular clinics. We reviewed records of all patients in our clinic with pediatric onset of symptoms who had WES done since 2013.

Effective Treatment With Albuterol in DOK7 Congenital Myasthenic Syndrome in Children.

Background: Congenital myasthenic syndromes consist of rare disorders resulting from mutations in genes encoding for presynaptic, synaptic, and postsynaptic proteins that are involved in the signal transmission of the neuromuscular junction. They are characterized by fatigable weakness of the skeletal muscles with symptom onset from birth to early childhood. DOK7 (downstream of tyrosine kinase 7) congenital myasthenic syndrome was previously treated successfully with ephedrine and salbutamol; however, both are unavailable in the United States.

Cerebellar ataxia, vertical supranuclear gaze palsy, sensorineural deafness, epilepsy, dementia, and hallucinations in an adolescent male.

We encountered an adolescent male with cerebellar ataxia since age 11, difficulty in vertical gaze from age 2, leg weakness since age 10, and partial epilepsy since age 8. At age 14, he developed visual and auditory hallucinations, as well as mild sensorineural deafness. He was evaluated as having a mitochondrial disorder.

Muscle disease.

On the basis of strong research evidence, Duchenne muscular dystrophy (DMD), the most common severe childhood form of muscular dystrophy, is an X-linked recessive disorder caused by out-of-frame mutations of the dystrophin gene. Thus, it is classified asa dystrophinopathy. The disease onset is before age 5 years.

Practice patterns of mitochondrial disease physicians in North America. Part 1: diagnostic and clinical challenges.

Mitochondrial medicine is a young subspecialty. Clinicians have a limited evidence base on which to formulate clinical decisions regarding diagnosis, treatment and patient management. Mitochondrial medicine specialists have cobbled together an informal set of rules and paradigms for preventive care and management based in part on anecdotal experience.

Childhood onset of limb-girdle muscular dystrophy.

Limb-girdle muscular dystrophies comprise a rare heterogeneous group of genetic muscular dystrophies, involving 15 autosomal recessive subtypes and seven autosomal dominant subtypes. Autosomal recessive dystrophy is far more common than autosomal dominant dystrophy. Typical clinical features include progressive limb muscle weakness and atrophy (proximal greater than distal), varying from very mild to severe.

Guanine triphosphate-cyclohydrolase 1-deficient dopa-responsive dystonia presenting as frequent falling in 2 children.

Guanine triphosphate (GTP)-cyclohydrolase 1 (GCH1)-deficient dopa-responsive dystonia is caused by GCH1 gene mutation. Two children presenting with frequent daily falling are reported with GCH1 gene mutations with persistent response to low-dose levodopa/carbidopa. Typical and atypical clinical features associated with GCH1 mutations are also reviewed.

Unexpected detection of dystrophin gene deletions by array comparative genomic hybridization.

Array comparative genomic hybridization has increasingly become the standard of care to evaluate patients for genomic imbalance. As the patient population evaluated by microarray expands, there is certain to be an increase in the detection of unexpected, yet common diseases. When array results predict a late-onset disorder or cancer predisposition, it becomes a challenge for physicians and counselors to adequately address with patients.

The efficacy of vagus nerve stimulation in intractable epilepsy associated with nonketotic hyperglycinemia in two children.

Nonketotic hyperglycinemia is an inborn error of glycine metabolism and these patients frequently suffer from intractable epilepsy despite treatment with sodium benzoate, dextromethophan, and multiple anticonvulsants. We encountered 2 infants with nonketotic hyperglycinemia whose intractable generalized convulsive seizures were difficult to control with sodium benzoate, dextromethophan, and multiple anticonvulsants. However, after the addition of vagus nerve stimulation, their intractable generalized seizures were >75% reduced in frequency, the numbers of multiple anticonvulsants were reduced, and the quality of life significantly improved.

Current trends in the treatment of infantile spasms.

Infantile spasms are an epilepsy syndrome with distinctive features, including age onset during infancy, characteristic epileptic spasms, and specific electroencephalographic patterns (interictal hypsarrhythmia and ictal voltage suppression). Adrenocorticotropic hormone (ACTH) was first employed to treat infantile spasms in 1958, and since then it has been tried in prospective and retrospective studies for infantile spasms. Oral corticosteroids were also used in a few studies for infantile spasms.

Partial epilepsy in an adolescent male with limb-girdle muscular dystrophy 1B.

Muscular dystrophies are inherited muscle disorders associated with different gene mutations. Fukuyama congenital muscular dystrophy is associated with cobblestone lissencephaly and epilepsy frequently. Rarely, other types of muscular dystrophies are also associated with epilepsy including Duchenne and Becker muscular dystrophy, facioscapulohumeral dystrophy, congenital muscular dystrophy with partial and complete deficiency of laminin alpha2 chain, and limb-girdle muscular dystrophy 2A with calpain deficiency.

Hypotonia, weakness, and pontocerebellar hypoplasia in siblings.

A 6-week-old girl presenting with severe weakness, hypotonia, gastroesophageal reflux, and microcephaly as well as dysmorphic features including micrognathia and high arched palate was also found to have pontocerebellar hypoplasia. She died of acute pneumonia at age 6 months. Her younger brother also had generalized hypotonia, weakness, areflexia, and tongue fasciculations and was also noted to have pontocerebellar hypoplasia revealed by brain magnetic resonance imaging.

Clinical variability in distal spinal muscular atrophy type 1 (DSMA1): determination of steady-state IGHMBP2 protein levels in five patients with infantile and juvenile disease.

Distal spinal muscular atrophy type 1 (DSMA1) is caused by mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene. Patients with DSMA1 present between 6 weeks and 6 months of age with progressive muscle weakness and respiratory failure due to diaphragmatic palsy. Contrary to this "classic" infantile disease, we have previously described a DSMA1 patient with juvenile disease onset.

Autistic disorder in 2 children with mitochondrial disorders.

Autistic disorder is a heterogeneous disorder. The majority of the cases are idiopathic, and only a small number of the autistic children have associated secondary diagnosis. This article reports 2 children with mitochondrial disorders associated with autistic disorder fulfilling the diagnostic criteria of the American Psychiatric Association Manual of Psychiatric Diseases, 4th edition, and briefly reviews the literature on autistic disorder associated with mitochondrial disorders.

Isolated neurosarcoidosis presenting as headache and multiple brain and spinal cord lesions mimicking central nervous system metastases.

Sarcoidosis is uncommon in children. Although isolated neurosarcoidosis has been seen in 15% adults with sarcoidosis, pediatric neurosarcoidosis is rarely reported. Neurosarcoidosis may present with cranial neuropathy, including facial palsy, optic nerve or other cranial nerve involvement, peripheral neuropathy, or manifestations of the central nervous system affecting the hypothalamus, pituitary gland, cerebral cortex, cerebellum, meninges, and spinal cord.

Coexisting muscular dystrophies and epilepsy in children.

Muscular dystrophies are composed of a variety of genetic muscle disorders linked to different chromosomes and loci and associated with different gene mutations that lead to progressive muscle atrophy and weakness. Fukuyama congenital muscular dystrophy is frequently associated with partial and generalized epilepsy and congenital brain anomalies, including cobblestone complex and other neuronal migration defects. We report generalized convulsive epilepsy in a boy with normal brain magnetic resonance imaging and Duchenne muscular dystrophy with deletion of dystrophin gene, and we report absence epilepsy with normal brain magnetic resonance imaging in another boy with limb girdle muscular dystrophy with partial calpain deficiency.

Effective treatment with oxcarbazepine in paroxysmal kinesigenic choreoathetosis.

Paroxysmal kinesigenic choreoathetosis is often responsive to anticonvulsants such as carbamazepine and phenytoin. We report a boy with paroxysmal kinesigenic choreoathetosis, which is dramatically relieved by oxcarbazepine even after unsatisfactory treatment with carbamazepine and other medications.

Leigh disease with mitochondrial DNA A8344G mutation: case report and brief review.

Leigh disease, subacute necrotizing encephalomyelopathy, is a neurodegenerative disorder often seen in infancy or childhood but rarely reported in adults. Genetic heterogeneity is well recognized, and the associated etiologies include both mitochondrial and nuclear DNA defects. We describe an infant presenting with developmental delay and then progressive multisystem disorder and neuroradiologic features of Leigh disease.