De novo, deleterious sequence variants that alter the transcriptional activity of the homeoprotein PBX1 are associated with intellectual disability and pleiotropic developmental defects.

We present eight patients with de novo, deleterious sequence variants in the PBX1 gene. PBX1 encodes a three amino acid loop extension (TALE) homeodomain transcription factor that forms multimeric complexes with TALE and HOX proteins to regulate target gene transcription during development. As previously reported, Pbx1 homozygous mutant mice (Pbx1-/-) develop malformations and hypoplasia or aplasia of multiple organs, including the craniofacial skeleton, ear, branchial arches, heart, lungs, diaphragm, gut, kidneys, and gonads. Clinical findings similar to those in Pbx mutant mice were observed in all patients with varying expressivity and severity, including external ear anomalies, abnormal branchial arch derivatives, heart malformations, diaphragmatic hernia, renal hypoplasia and ambiguous genitalia. All patients but one had developmental delays. Previously reported patients with congenital anomalies affecting the kidney and urinary tract exhibited deletions and loss of function variants in PBX1. The sequence variants in our cases included missense substitutions adjacent to the PBX1 homeodomain (p.Arg184Pro, p.Met224Lys, and p.Arg227Pro) or within the homeodomain (p.Arg234Pro, and p.Arg235Gln), whereas p.Ser262Glnfs*2, and p.Arg288* yielded truncated PBX1 proteins. Functional studies on five PBX1 sequence variants revealed perturbation of intrinsic, PBX-dependent transactivation ability and altered nuclear translocation, suggesting abnormal interactions between mutant PBX1 proteins and wild-type TALE or HOX cofactors. It is likely that the mutations directly affect the transcription of PBX1 target genes to impact embryonic development. We conclude that deleterious sequence variants in PBX1 cause intellectual disability and pleiotropic malformations resembling those in Pbx1 mutant mice, arguing for strong conservation of gene function between these two species.

Clinical trial readiness in non-ambulatory boys and men with duchenne muscular dystrophy: MDA-DMD network follow-up.

INTRODUCTION: Outcomes sensitive to change over time in non-ambulatory boys/men with Duchenne muscular dystrophy (DMD) are not well-established. METHODS: Subjects (n = 91; 16.8 ± 4.5 years old) were assessed at baseline and 6-month intervals for 2 years. We analyzed all subjects using an intent-to-treat model and a subset of stronger subjects with Brooke Scale score ≤4, using repeated measures. RESULTS: Eight patients (12-33 years old) died during the study. Sixty-six completed 12-month follow-up, and 51 completed 24-month follow-up. Those taking corticosteroids performed better at baseline, but rates of decline were similar. Forced vital capacity percent predicted (FVC% predicted) declined significantly only after 2 years. However, Brooke and Egen Klassifikation (EK) Scale scores, elbow flexion, and grip strength declined significantly over both 1 and 2 years. CONCLUSION: Brooke and EK Scale scores, elbow flexion, and grip strength were outcomes most responsive to change. FVC% predicted was responsive to change over 2 years. Corticosteroids benefited non-ambulatory DMD subjects but did not affect decline rates of measures tested here. Muscle Nerve 54: 681-689, 2016.

Outcome reliability in non-ambulatory boys/men with Duchenne muscular dystrophy.

INTRODUCTION: Therapeutic trials in Duchenne muscular dystrophy (DMD) often exclude non-ambulatory individuals. Here we establish optimal and reliable assessments in a multicenter trial. METHODS: Non-ambulatory boys/men with DMD (N = 91; 16.7 ± 4.5 years of age) were assessed by trained clinical evaluators. Feasibility (percentage completing task) and reliability [intraclass correlation coefficients (ICCs) between morning and afternoon tests] were measured. RESULTS: Forced vital capacity (FVC), assessed in all subjects, showed a mean of 47.8 ± 22% predicted (ICC 0.98). Brooke Upper Extremity Functional Rating (Brooke) and Egen Klassifikation (EK) scales in 100% of subjects showed ICCs ranging from 0.93 to 0.99. Manual muscle testing, range of motion, 9-hole peg test, and Jebsen-Taylor Hand Function Test (JHFT) demonstrated varied feasibility (99% to 70%), with ICCs ranging from 0.99 to 0.64. We found beneficial effects of different forms of corticosteroids for the Brooke scale, percent predicted FVC, and hand and finger strength. CONCLUSIONS: Reliable assessment of non-ambulatory boys/men with DMD is possible. Clinical trials will have to consider corticosteroid use.

Acute Transverse Myelitis Caused by Echovirus 11 in a Pediatric Patient: Case Report and Review of the Current Literature.

A 12-year-old boy presented with acute flaccid weakness of the right upper extremity and was found to have acute flaccid myelitis with transverse myelitis involving the cervical cord (C1-T1). An interdisciplinary team-based approach was undertaken, including input from a generalist, an infectious diseases physician, and a pediatric neurologist. Consultation was sought from the Minnesota Department of Health to investigate for a potential etiology and source of the responsible infection. Evaluation for an infectious etiology demonstrated infection with human echovirus 11. The patient recovered with some disability. Echovirus 11 is among the more common etiologies of acute flaccid myelitis and should be considered in the differential diagnosis of this increasingly recognized pediatric infection.

Infantile Epileptic Encephalopathy Associated With SCN2A Mutation Responsive to Oral Mexiletine.

BACKGROUND: Genetic alterations are significant causes of epilepsy syndromes; especially early-onset epileptic encephalopathies and voltage-gated sodium channelopathies are among the best described. Mutations in the SCN2A subunit of voltage-gated sodium channels have been associated with benign familial neonatal-infantile seizures, generalized epilepsy febrile seizures plus, and an early-onset infantile epileptic encephalopathy. METHOD: We describe two infants with medically refractory seizures due to a de novo SCN2A mutation. RESULTS: The first child responded to intravenous lidocaine with significant reduction in seizure frequency and was successfully transitioned to enteral mexiletine. Mexiletine was subsequently used in a second infant with reduction in seizure frequency. CONCLUSION: Class 1b antiarrhythmic agents, lidocaine and mexiletine, may be useful in infants with medically refractory early infantile epileptic encephalopathy secondary to mutations in SCN2A.

Adoptive protection from experimental myasthenia gravis with T cells from mice treated nasally with acetylcholine receptor epitopes.

Nasal administration of synthetic CD4(+) epitopes of the acetylcholine receptor (AChR) prevents experimental myasthenia gravis (EMG) in C57Bl/6 mice, but not in IL4-deficient C57Bl/6 (IL4(-/-)) mice. Here we verify that nasal tolerance requires IL4, by showing that CD4(+) cells from C57Bl/6 mice treated nasally with a pool of AChR CD4(+) epitopes protected IL4(-/-) mice from EMG and caused a reduced production of anti-AChR antibody. CD4(+) cells from C57Bl/6 mice treated with unrelated peptides or sham-treated did not induce protection. CD4(+) cells from C57Bl/6 mice treated with just one AChR peptide protected IL4(-/-) mice from EMG without affecting antibody synthesis.

One year outcome of boys with Duchenne muscular dystrophy using the Bayley-III scales of infant and toddler development.

BACKGROUND: The pathogenesis of Duchenne muscular dystrophy starts before birth. Despite this, clinical trials exclude young boys because traditional outcome measures rely on cooperation. We recently used the Bayley-III Scales of Infant and Toddler Development to study 24 infants and boys with Duchenne muscular dystrophy. Clinical evaluators at six centers were trained and certified to perform the Bayley-III. Here, we report 6- and 12-month follow-up of two subsets of these boys. PATIENTS: Nineteen boys (1.9 ± 0.8 years) were assessed at baseline and 6 months. Twelve boys (1.5 ± 0.8 years) were assessed at baseline, 6, and 12 months. RESULTS: Gross motor scores were lower at baseline compared with published controls (6.2 ± 1.7; normal 10 ± 3; P < 0.0001) and revealed a further declining trend to 5.7 ± 1.7 (P = 0.20) at 6 months. Repeated measures analysis of the 12 boys monitored for 12 months revealed that gross motor scores, again low at baseline (6.6 ± 1.7; P < 0.0001), declined at 6 months (5.9 ± 1.8) and further at 12 months (5.3 ± 2.0) (P = 0.11). Cognitive and language scores were lower at baseline compared with normal children (range, P = 0.002-<0.0001) and did not change significantly at 6 or 12 months (range, P = 0.89-0.09). Fine motor skills, also low at baseline, improved >1 year (P = 0.05). CONCLUSION: Development can reliably be measured in infants and young boys with Duchenne muscular dystrophy across time using the Bayley-III. Power calculations using these data reveal that motor development may be used as an outcome measure.

Motor and cognitive assessment of infants and young boys with Duchenne Muscular Dystrophy: results from the Muscular Dystrophy Association DMD Clinical Research Network.

Therapeutic trials in Duchenne Muscular Dystrophy (DMD) exclude young boys because traditional outcome measures rely on cooperation. The Bayley III Scales of Infant and Toddler Development (Bayley III) have been validated in developing children and those with developmental disorders but have not been studied in DMD. Expanded Hammersmith Functional Motor Scale (HFMSE) and North Star Ambulatory Assessment (NSAA) may also be useful in this young DMD population. Clinical evaluators from the MDA-DMD Clinical Research Network were trained in these assessment tools. Infants and boys with DMD (n = 24; 1.9 ± 0.7 years) were assessed. The mean Bayley III motor composite score was low (82.8 ± 8; p ≤ .0001) (normal = 100 ± 15). Mean gross motor and fine motor function scaled scores were low (both p ≤ .0001). The mean cognitive comprehensive (p=.0002), receptive language (p ≤ .0001), and expressive language (p = .0001) were also low compared to normal children. Age was negatively associated with Bayley III gross motor (r = -0.44; p = .02) but not with fine motor, cognitive, or language scores. HFMSE (n=23) showed a mean score of 31 ± 13. NSAA (n = 18 boys; 2.2 ± 0.4 years) showed a mean score of 12 ± 5. Outcome assessments of young boys with DMD are feasible and in this multicenter study were best demonstrated using the Bayley III.