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. In our cohort, onasemnogene abeparvovec treatment remained safe and no child experienced any significant adverse events, including thrombotic microangiopathy, liver failure or death. All children experienced benefit, although the benefit in those with 2 copies of SMN2 was variable. 79 % of the children treated when symptomatic had a SMN2 modifying therapy added on. With careful screening and post treatment monitoring, onasemnogene abeparvovec is safe and effective for children with SMA in the state of Ohio, but more work needs to be done to ensure optimal outcomes for all children with 2 copies of SMN2.

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. Functional studies using yeast complementation assays support a loss-of-function effect for both variants; however, this did not reveal variable effects that might explain the phenotypic differences. These cases expand the mutational spectrum of GARS1-related disorders and demonstrate phenotypic variability based on the specific substitution at a single residue.

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. METHODS: Patients with genetically confirmed SMA completed functional testing at each visit including the Neuromuscular GRO and other appropriate gross motor outcomes. RESULTS: We enrolled 91 patients with SMA types 1 to 3 between 8 days and 32.1 years. The GRO utilizes a 0- to 2-point scale with scores in our cohort ranging from 1 to 95 points with no floor or ceiling effect. GRO scores were significantly different across functional categories (P < 0.001) and treatment status (P = 0.01) and correlated to other functional assessments (P ≤ 0.001). All patients were measured using the GRO, whereas traditional outcomes were only appropriate on 36% to 59% of our cohort. CONCLUSION: The Neuromuscular GRO quantifies function across the span of age and abilities included in our cohort, allowing for continuous longitudinal monitoring on one scale to reduce the burden of testing in our heterogeneous clinic population.

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. METHODS: The purpose of our study was to define the natural history in boys aged from ≥3 to <8 years using the North Star Ambulatory Assessment (NSAA), 100-meter timed test (100m), 10-meter walk/run (10m), time to rise (Rise), and 4-stair climb (4SC). Assessments were completed as standard of care during regularly scheduled clinic visits. RESULTS: One hundred sixty-two boys with DMD aged 3.1 to 7.9 years on glucocorticoids were evaluated using one or more of the following tests as appropriate for age: NSAA (N = 158; 3.1-7.9 years), 100m (N = 131; 3.4-7.9 years), 10m (N = 162; 3.1-7.9 years), Rise (N = 160; 3.1-7.9 years), and 4SC (N = 153; 3.1-7.9 years). Longitudinal data are presented by age in a subcohort (N = 64). CONCLUSIONS: Our study documents the baseline function of boys with DMD who are being treated with corticosteroids. These data will be useful to compare ongoing and future therapeutic intervention(s) for DMD.

Gene Therapy for Spinal Muscular Atrophy: Safety and Early Outcomes.

BACKGROUND AND OBJECTIVES: Historically, autosomal recessive 5q-linked spinal muscular atrophy (SMA) has been the leading inherited cause of infant death. SMA is caused by the absence of the SMN1 gene, and SMN1 gene replacement therapy, onasemnogene abeparvovec-xioi, was Food and Drug Administration approved in May 2019. Approval included all children with SMA age <2 years without end-stage weakness. However, gene transfer with onasemnogene abeparvovec-xioi has been only studied in children age ≤8 months. METHODS: In this article, we report key safety and early outcome data from the first 21 children (age 1-23 months) treated in the state of Ohio. RESULTS: In children ≤6 months, gene transfer was well tolerated. In this young group, serum transaminase (aspartate aminotransferase and alanine aminotransferase) elevations were modest and not associated with γ glutamyl transpeptidase elevations. Initial prednisolone administration matched that given in the clinical trials. In older children, elevations in aspartate aminotransferase, alanine aminotransferase and γ glutamyl transpeptidase were more common and required a higher dose of prednisolone, but all were without clinical symptoms. Nineteen of 21 (90%) children experienced an asymptomatic drop in platelets in the first week after treatment that recovered without intervention. Of the 19 children with repeated outcome assessments, 11% (n = 2) experienced stabilization and 89% (n = 17) experienced improvement in motor function. CONCLUSIONS: In this population, with thorough screening and careful post-gene transfer management, replacement therapy with onasemnogene abeparvovec-xioi is safe and shows promise for early efficacy.

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). Participants completed ACTIVE, other traditional assessments, and patient-reported outcomes. Responsiveness to change was evaluated by comparing longitudinal data on untreated participants to those receiving Spinraza. RESULTS: ACTIVE was significantly correlated to the Hammersmith Functional Motor Scales Expanded and Revised Upper Limb Module (ρ=0.85 and ρ=0.92 respectively; p<0.001). Relevance to patients and families was established by strong correlations to the Patient Reported Outcomes Measurement Information System self- and parent proxy-measures of upper extremity ability (ρ=0.63 and ρ=0.70 respectively; p<0.001). Responsiveness to change was demonstrated by significant change in scaled scores after treatment (median 15.9 points, Wilcoxon signed-rank test p<0.01). A preliminary minimum clinically important difference is presented. INTERPRETATION: These results suggest that ACTIVE WSV scores are a meaningful assessment with which to quantify change over time in individuals with SMA types 2 and 3. WHAT THIS PAPER ADDS: Ability Captured Through Interactive Video Evaluation (ACTIVE) quantifies upper extremity function in spinal muscular atrophy. ACTIVE's scaled workspace volume strongly correlates to self- and parent-report of function. ACTIVE quantifies meaningful change after treatment.

HABILIDAD CAPTURADA A TRAVÉS DE LA EVALUACIÓN DE VIDEO INTERACTIVA (ACTIVE) DEL VOLUMEN DE TRABAJO DE VIDEOJUEGO PARA CUANTIFICAR UN CAMBIO SIGNIFICATIVO EN LA ATROFIA MUSCULAR ESPINAL: OBJETIVO: Evaluar la utilidad de la Habilidad Capturada a través de la Evaluación de Video Interactiva (ACTIVE) escalada para cuantificar un cambio significativo en individuos con atrofia muscular espinal (SMA) tipos 2 o 3 debido a la progresión de la enfermedad o el tratamiento. METHOD: ACTIVE es un videojuego diseñado a medida que mide el volumen del espacio de trabajo (WSV). Los participantes incluyeron 62 individuos con SMA (edad media [SD] 10 años 9 meses [5 años], rango 2 años 9 meses - 24 años) y 362 controles de frecuencia correspondiente (edad media [SD] 10 años 9 meses [3 años 6 meses], rango 3 años 2 meses - 24 años 9 meses). Los participantes completaron ACTIVE, otras evaluaciones tradicionales y los resultados informados por pacientes. La capacidad de respuesta al cambio se evaluó comparando los datos longitudinales de los participantes no tratados con los que recibieron Spinraza. RESULTADOS: ACTIVE se correlacionó significativamente con las Escalas de Motoras Funcionales de Hammersmith y el Módulo de Miembro Superior Revisado (Rho = 0,85 y 0,92 respectivamente; p<0,001). La relevancia para los pacientes y las familias se estableció mediante fuertes correlaciones con las medidas aproximadas propias y parentales de la capacidad de la extremidad superior (Rho = 0,63 y 0,70 respectivamente; p<0,001). La capacidad de respuesta al cambio se demostró mediante un cambio significativo en las puntuaciones escaladas después del tratamiento (mediana de 15,9 puntos, prueba de rango con signo de Wilcoxon p<0,01). Se presenta una diferencia clínicamente importante preliminar mínima. INTERPRETACIÓN: Estos resultados sugieren que las puntuaciones ACTIVE WSV son una evaluación significativa con la cual se puede cuantificar el cambio a lo largo del tiempo en individuos con SMA tipos 2 y 3.

HABILIDADE CAPTURADA POR MEIO DE AVALIAÇÃO VÍDEO-INTERATIVA (ACTIVE) DO VOLUME ESPAÇO DE TRABALHO DE VÍDEO GAME PARA QUANTIFICAR MUDANÇA SIGNIFICATIVA EM ATROFIA MUSCULAR ESPINHAL: OBJETIVO: Avaliar a utilidade dos escores escalares da Habilidade capturada por avaliação vídeo-interativa (ACTIVE) para quantificar mudança significativa devido à progressão da doença ou tratamento em indivíduos com atrofia muscular espinhal (AME) tipos 2 ou 3. MÉTODO: ACTIVE é um vídeo game projetado individualmente que mensura o volume do espaço de trabalho (VET). Os participantes incluíram 62 indivíduos com AME (média de idade [DP] 10a 9m [5a], variação de 2a 9m-24a) e 362 controles pareados por frequência (média de idade [DP] 10a 9m [3a 6m], variação de 3a 2m-24a 9m). Os participantes completaram o ACTIVE, outras avaliações tradicionais, e resultados relatados por pacientes. A responsividade à mudança foi avaliada comparando dados longitudinais de pacientes não tratados em relação àqueles recebendo Spinraza. RESULTADOS: ACTIVE foi significativamente correlacionado com as Escalas Motoras Funcinais Hammersmith e o Módulo de Membro superior revisado (Rho=0,85 e 0,92 respectivamente; p<0,001). A relevância para pacientes e famílias foi estabelecida por fortes correlações com o Sistema de medida de informação de resultados relatados por pacientes (medidas auto-relatadas e relatadas por pais) da capacidade do membro superior (Rho=0,63 e 0,70 respectivamente; p<0,001). A responsividade à mudança foi demonstrada por mudanca significativa nos escores escalares após o tratamento (mediana 15,9 pontos, teste de Wilcoxon signed-rank p<0,01). Uma medida preliminar de mínima diferença clinicamente importante é apresentada. INTERPRETAÇÃO: Estes resultados sugerem que os escores de VET ACTIVE são uma avaliação significativa com a qual quantificar mudança com o passar do tempo em indivíduos com AME tipos 2 e 3.

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. Patients were included if clinical suspicion was high for a neuromuscular disease. Clinical WES was performed in 30 families, representing 31 patients, all of whom were seen for hypotonia, weakness, or gait disturbance. Probands had between 2 and 12 genetic diagnostic tests prior to obtaining WES. A genetic diagnosis was established in 11 families (37%), and in 12 patients (39%), with mutations in 10 different genes. Five of these genes have only been associated with disease since 2013, and were not previously represented on clinically available disease gene panels. Our results confirm the utility of WES in the clinical setting, particularly for genetically heterogeneous syndromes. The availability of WES can provide an end to the diagnostic odyssey for parents and allow for expansion of phenotypes.

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. METHODS: Case report of a child with muscle weakness. RESULTS: This report describes a boy who presented only with progressive limb-girdle muscle weakness since age 2 years. The muscle biopsy with extensive studies revealed no obvious etiologies. His muscle weakness rapidly worsened, requiring a wheelchair for daily activities. Expanded neuromuscular gene panel promptly led to the diagnosis of DOK7 congenital myasthenic syndrome, and his muscle strength dramatically and persistently improved in four weeks with albuterol treatment, allowing him to walk independently. In a brief literature review, 15 patients (five treated between ages 5 and 17 years) from the Mayo Clinic with DOK7 mutations were also successfully treated with albuterol. CONCLUSION: DOK7 congenital myasthenic syndrome often presents with limb-girdle muscle weakness, which can become progressive without proper treatment. If muscle biopsy reveals no obvious etiology, an expanded neuromuscular gene panel may lead to a specific diagnosis of congenital myasthenic syndrome such as those due to DOK7 mutation. Albuterol is often used to treat bronchial asthma; however, it can also dramatically and persistently improve the muscle strength of DOK7 congenital myasthenic syndrome.

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. No common mitochondrial DNA mutations were detected in the blood. Muscle biopsy revealed nonspecific changes and normal respiratory chain enzyme complexes. He developed progressive cognitive decline leading to diagnosis of dementia at age 15, and intractablepartial epilepsy persisted despite treatment with multiple anticonvulsants. He also had progressive dysphagia requiring gastrostomy tube for nutrition. He required many other diagnostic investigations for neurodegenerative disorders, but was eventually confirmed as having Niemann-Pick disease type C with excessive free cholesterol using filipin staining and zero activity for cholesterol esterification in fibroblast as well as two pathogenic mutations in the NPC1 gene.

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. Patients with DMD present with progressive symmetrical limb-girdle muscle weakness and become wheelchair dependent after age 12 years. (2)(3). On the basis of some research evidence,cardiomyopathy and congestive heart failure are usually seen in the late teens in patients with DMD. Progressive scoliosis and respiratory in sufficiency often develop once wheelchair dependency occurs. Respiratory failure and cardiomyopathy are common causes of death, and few survive beyond the third decade of life. (2)(3)(4)(5)(6)(7). On the basis of some research evidence, prednisone at 0.75 mg/kg daily (maximum dose, 40 mg/d) or deflazacort at 0.9 mg/kg daily (maximum dose, 39 mg/d), a derivative of prednisolone (not available in the United States), as a single morning dose is recommended for DMD patients older than 5 years, which may prolong independent walking from a few months to 2 years. (2)(3)(16)(17). Based on some research evidence, treatment with angiotensin-converting enzyme inhibitors, b-blockers, and diuretics has been reported to be beneficial in DMD patients with cardiac abnormalities. (2)(3)(5)(18). Based on expert opinion, children with muscle weakness and increased serum creatine kinase levels may be associated with either genetic or acquired muscle disorders (Tables 1 and 3). (14)(15)

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. The Mitochondrial Medicine Society (MMS) assessed the current state of clinical practice from diagnosis, to preventive care and treatment, as provided by various mitochondrial disease specialists in North America. We hope that by obtaining this information we can begin moving towards formulating a set of consensus criteria and establishing standards of care.

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. Significant overlap of clinical phenotypes, with genetic and clinical heterogeneity, constitutes the rule for this group of diseases. Muscle biopsies are useful for histopathologic and immunolabeling studies, and DNA analysis is the gold standard to establish the specific form of muscular dystrophy. A definitive diagnosis among various subtypes is challenging, and the data presented here provide neuromuscular clinicians with additional information to help attain that goal.

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. Included in this study were three patients described with nonspecific phenotypic findings who underwent microarray testing to better define their disease etiology. An unexpected deletion within the dystrophin gene was observed in each case, despite that no patient was suspected of a dystrophinopathy at the time of testing. The patients included an 8-day-old male with a dystrophin deletion predictive of Becker muscular dystrophy, an 18-month old female found to be the carrier of deletion, and a 4-year-8-month-old male with a deletion predictive of Duchenne muscular dystrophy. In this circumstance it becomes difficult to counsel the family, as well as to predict disease course when underlying medical conditions may exist. However, early detection may enable the patient to receive proactive treatment, and allows for screening of at-risk family members. Ultimately, it is up to the clinician to promote informed decision-making within the family prior to testing, and ensure that adequate counseling is provided during follow-up.

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. The efficacy in seizure reduction persists for at least 3 years in both children.

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. Variable success in cessation of infantile spasms and normalization of electroencephalograms was demonstrated. However, frequent significant adverse effects are associated with ACTH and oral corticosteroids. Vigabatrin has been used since the 1990s, and shown to be successful in resolution of infantile spasms, especially for infantile spasms associated with tuberous sclerosis. It is associated with visual field constriction, which is often asymptomatic and requires perimetric visual field study to identify. When ACTH, oral corticosteroids, and vigabatrin fail to induce cessation of infantile spasms, other alternative treatments include valproic acid, nitrazepam, pyridoxine, topiramate, zonisamide, lamotrigine, levetiracetam, felbamate, ganaxolone, liposteroid, thyrotropin-releasing hormone, intravenous immunoglobulin and a ketogenic diet. Rarely, infantile spasms in association with biotinidase deficiency, phenylketonuria, and pyridoxine-dependent seizures are successfully treated with biotin, a low phenylalanine diet, and pyridoxine, respectively. For medically intractable infantile spasms, some properly selected patients may have complete cessation of infantile spasms with appropriate surgical treatments.

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. We now report another rare case of partial epilepsy and limb-girdle muscular dystrophy type 1B with lamin A/C gene mutation.

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. In this paper, we present (1) a second juvenile case and (2) the first study of DSMA1 on protein level in patients with infantile (n = 3) as well as juvenile (n = 2) disease onset observing elevated residual steady-state IGHMBP2 protein levels in the patients with late onset DSMA1 as compared to those with classic DSMA1. Mutation screening in IGHMBP2 revealed two patients compound heterozygous for a novel missense mutation (c.1478C-->T; p.T493I) and another previously described mutation. In lymphoblastoid cells of both patients, steady-state IGHMBP2 protein levels were reduced. In comparison to wild-type IGHMBP2, the p.T493I variant protein had an increased tendency to aggregate and spontaneously degrade in vitro. We verified a change in the physicochemical properties of the p.T493I variant which may explain the pathogenicity of this mutation. Our data further suggest that the age of onset of DSMA1 is variable, and we discuss the effect of residual IGHMBP2 protein levels on the clinical course and the severity of the disease.

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. We herein briefly review familial spinal muscular atrophy with type 1 pontocerebellar hypoplasia in children.

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.