Ann M. Neumeyer

Understanding relationships between autism, intelligence, and epilepsy: a cross-disorder approach

Aim  As relationships between autistic traits, epilepsy, and cognitive functioning remain poorly understood, these associations were explored in the biologically related disorders tuberous sclerosis complex (TSC), neurofibromatosis type 1 (NF1), and epilepsy.

Arterial delivery of myoblasts to skeletal muscle

One of the major limitations of myoblast implantation as a therapy for muscular disease is that multiple injections by intramuscular implantation may be required for widespread delivery of cells. Also, some sites (eg, the diaphragm) are relatively inaccessible to injection. As an alternative, we have undertaken intra-arterial administration of myoblasts. For these experiments, we used donor cell myoblasts from the immortal L6 cell line labeled with lacZ via the β-gal-at-gal retrovirus. In our model, target rat skeletal muscle (tibialis anterior [TA]) was injured using 0.5 ml of 0.5% bupivacaine and 15 IU of hyaluronidase; saline was injected into the contralateral side as a control. We infused 3 × 106 lacZ-positive cells into the abdominal aorta of previously injured, immunosuppressed (cyclosporine A) rats. At 7, 14, and 28 days, TA, liver, heart, lung, and spleen were examined for lacZ staining. In both the injured and control muscles, a few differentiated, lacZ-positive muscle cells were present, both singly and in groups, at each time point. These studies demonstrate that genetically labeled, transformed myoblasts may migrate from the arterial circulation to muscle and fuse there to form differentiated muscle cells. It is conceivable that intraarterial delivery of myoblasts may have a role in the therapy of selected diseases of skeletal muscle.

Pilot study of myoblast transfer in the treatment of Becker muscular dystrophy

We evaluated myoblast implantation therapy in three subjects with Becker muscular dystrophy who received 60 million myoblasts in one tibialis anterior(TA) muscle 2 months after beginning cyclosporine immunosuppression (5 to 10 mg/kg) that continued for 1 year. Strength of the implanted and control TA muscles was measured before and after treatment using a gauge to record TA contraction force. Our protocol controlled for the effects of cyclosporine and myoblast injections. In this pilot, myoblast implantation did not improve strength of the implanted TA muscles.

Large genomic deletions: A novel cause of Ullrich congenital muscular dystrophy

Two mutational mechanisms are known to underlie Ullrich congenital muscular dystrophy (UCMD): heterozygous dominant negatively‐acting mutations and recessively‐acting loss‐of‐function mutations. We describe large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD in 2 families. Clinically unaffected parents carrying large genomic deletions of COL6A1and COL6A2also provide conclusive evidence that haploinsufficiency for COL6A1and COL6A2is not a disease mechanism for Bethlem myopathy. Our findings have important implications for the genetic evaluation of patients with collagen VI–related myopathies as well as for potential therapeutic interventions for this patient population. Ann Neurol 2011;69:206–211

Identification of two mutations and a polymorphism in the chloride channel CLCN-1 in patients with Becker's generalized myotonia

ABSTRACT Myotonia congenita is an inherited muscle disorder characterized by muscle stiffness and hypertrophy. Its clinical phenotype depends, in part, on whether it is inherited as a dominant or recessive trait, respectively designated Thomsens disease or Beckers generalized myotonia (BGM). In either case, it is associated with abnormalities in the muscle currents that are linked to the gene (CLCN-1) on human chromosome 7q35 encoding the skeletal muscle chloride channel. Single-strand conformation polymorphism analysis was used to screen two families with the BGM for mutations in the CLCN-1 gene. Two new mutations were found (G 201ins and A317Q). The latter mutation has been previously described in Thomsens disease.

Developmental changes in expression of myotonic dystrophy protein kinase in the rat central nervous system

Myotonic dystrophy protein kinase (DMPK) is the protein product of the genetic locus associated with myotonic dystrophy, in which alterations of muscle excitability, cardiac conduction defects, mental retardation, and cognitive deficiencies are inherited as an autosomal dominant trait. DMPK belongs to a novel protein serine/threonine kinase family, but its regulation and physiological functions have not been specified. In a first step toward understanding the functions of DMPK in the central nervous system, we have characterized its localization and developmental pattern of expression in rat brain and spinal cord by using a monospecific rabbit antiserum produced against bacterially expressed DMPK. Expression of DMPK begins after birth and increases gradually to peak at postnatal day 21 with antibody labeling of neuronal cell types in many regions. After postnatal day 21 and proceeding to the adult, the pattern of expression becomes more restricted, with localization to certain regions or cell groups in the central nervous system. Electron microscopy reveals localization within adult spinal motor neurons to the endoplasmic reticulum and dendritic microtubules. The adult localizations suggest that DMPK may function in membrane trafficking and secretion within neurons associated with cognition, memory, and motor control. J. Comp. Neurol. 394:309–325, 1998.

Retrial of Selective Serotonin Reuptake Inhibitors in Children with Pervasive Developmental Disorders: A Retrospective Chart Review

BACKGROUND Youths with pervasive developmental disorders (PDDs) often have symptoms that fail to respond to selective serotonin reuptake inhibitor (SSRI) treatment. These children may be given a subsequent trial of another SSRI. This study reports on the outcome of PDD youths who received a second SSRI trial after an initial treatment failure. METHODS Clinic charts were reviewed for 22 outpatient youths with a DSM-IV diagnosis of a PDD who were treated with an SSRI after an initial failure with a previous SSRI. Response for the second SSRI trial was determined using the Clinical Global Impressions-Improvement Scale (CGI-I). Treatment indications, symptom severity, demographic data, and side effects were recorded. RESULTS For the second SSRI trial, 31.8% of the subjects were rated as much improved on the CGI-I scale and determined to be responders, with 68.2% of the subjects demonstrating activation side effects. 90% of subjects demonstrated activation side effects when data from both SSRI trials were combined. There were no statistically significant associations between outcome of the second SSRI trial and clinical/demographic variables. CONCLUSIONS A second trial of an SSRI after an initial SSRI treatment failure was often unsuccessful in children and adolescents with PDDs. Activation side effects were common. Because alternative treatments in this population are limited, a second trial of an SSRI may still be considered. The study was limited by its retrospective design and by its small sample size.

A Pilot Study of Autism-Specific Care Plans During Hospital Admission.

BACKGROUND AND OBJECTIVE: Hospital admissions can be difficult for patients with autism spectrum disorder (ASD). We created an autism-specific care plan (ACP) to help improve the hospital experience for patients with ASD, and we tested feasibility and acceptability and compared the experience of care for children with and without an ACP. METHODS: We performed a nonrandomized, retrospective chart review of all patients with ASD and a hospital admission from January 2013 to December 2013 (n = 142) to determine feasibility of the intervention. We then mailed surveys to all 142 families to measure experience with the ACP and to compare experience of care in those who did and did not have an ACP. Using multivariable linear regression we assessed the association of experience of care with ACP use while adjusting for covariates. RESULTS: The ACP was well tolerated by parents and used frequently by staff. Compared with parents who did not use the ACP, parents who used the ACP reported a better experience relating to their general hospital experience (B = 1.48, P < .001) and staff attention to their child’s ASD-specific needs (B = 3.07, P < .001). CONCLUSIONS: According to this pilot study, care plans are feasible and hold promise to improve the experience of care for children with ASD and their families in the hospital setting.

Bone Accrual in Males with Autism Spectrum Disorder

Objective To test the hypothesis that bone accrual over a 4‐year period is reduced in boys with autism spectrum disorder (ASD) compared with typically developing controls. Study design Twenty‐five boys with ASD and 24 controls were assessed for bone outcomes. Fourteen boys with ASD and 11 controls were assessed both at baseline and after 4 years. The mean subject age was 11.0 ± 1.6 years at study initiation and 14.9 ± 1.6 years at follow‐up. Bone mineral density (BMD) was measured at the spine, hip, and whole body using dual‐energy X‐ray absorptiometry and normalized for age, race, and sex (BMD z‐scores). Height adjustments were performed as well. We assessed medical history, physical activity using questionnaires, vitamin D and calcium intake using food records, and serum calcium, phosphorus, 25(OH)‐vitamin D, and pubertal hormone levels. Results Boys with ASD had lower spine, hip, and whole body BMD z‐scores compared with controls. In those subjects assessed both at baseline and after 4 years, bone accrual rates did not differ between the 2 groups; however, spine and hip BMD z‐scores remained lower in the boys with ASD than in controls at follow‐up. Notably, the ASD group was less physically active at both time points. Conclusion Although pubertal bone accrual was similar to that in controls, BMD in children with ASD remained low over a 4‐year follow‐up period, suggesting that low BMD is a consequence of prepubertal factors, such as low physical activity. Studies are needed to investigate the causes and consequences of decreased BMD, to assess BMD in females and adults with ASD, and to evaluate therapeutic interventions.

Feasibility of Conducting Autism Biomarker Research in the Clinical Setting

Objective: Recruitment and completion of research activities during regular clinical care has the potential to increase research participation in complex neurodevelopmental disorders. We evaluated the feasibility, and effect on clinical care, of conducting biomarker research within a subspecialty clinical visit for autism spectrum disorder (ASD). Methods: Children, aged 5 to 10 years, were recruited by providers in ASD clinics at 5 institutions. Biomarkers collected were growth measurements, head circumference, neurologic and dysmorphology examinations, digit ratio (2D:4D) measurement, and platelet serotonin and urinary melatonin sulfate excretion levels. Parents completed the Aberrant Behavior Checklist—Community and a medical/demographic questionnaire. Cognitive level was abstracted from the medical record. Parents and clinicians completed surveys on the effect of the study on the clinical visit. Results: Eighty-three children and their caregivers participated. Factors limiting participation included difficulty reaching families by phone and parent concern about the study blood draw requirement. All children completed at least 4 of 7 planned research activities. Demographic factors, educational placement, and child behavior were not associated with completion of study activities. Lower nonverbal cognitive function was weakly associated with fewer activities completed. Forty-four percent of clinicians reported an effect of the research study on the clinical visit. However, neither parent-reported nor clinician-reported effect was associated with the degree of study activity completion. Conclusion: Recruiting study participants in the context of scheduled ASD clinical visits required significant effort. However, once recruited, participants completed most study activities, regardless of behavioral symptom severity. Research activities did not adversely affect the clinical visit.