Enzyme-replacement therapy in life-threatening hypophosphatasia.

BACKGROUND: Hypophosphatasia results from mutations in the gene for the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Inorganic pyrophosphate accumulates extracellularly, leading to rickets or osteomalacia. Severely affected babies often die from respiratory insufficiency due to progressive chest deformity or have persistent bone disease. There is no approved medical therapy. ENB-0040 is a bone-targeted, recombinant human TNSALP that prevents the manifestations of hypophosphatasia in Tnsalp knockout mice. METHODS: We enrolled infants and young children with life-threatening or debilitating perinatal or infantile hypophosphatasia in a multinational, open-label study of treatment with ENB-0040. The primary objective was the healing of rickets, as assessed by means of radiographic scales. Motor and cognitive development, respiratory function, and safety were evaluated, as well as the pharmacokinetics and pharmacodynamics of ENB-0040. RESULTS: Of the 11 patients recruited, 10 completed 6 months of therapy; 9 completed 1 year. Healing of rickets at 6 months in 9 patients was accompanied by improvement in developmental milestones and pulmonary function. Elevated plasma levels of the TNSALP substrates inorganic pyrophosphate and pyridoxal 5'-phosphate diminished. Increases in serum parathyroid hormone accompanied skeletal healing, often necessitating dietary calcium supplementation. There was no evidence of hypocalcemia, ectopic calcification, or definite drug-related serious adverse events. Low titers of anti-ENB-0040 antibodies developed in four patients, with no evident clinical, biochemical, or autoimmune abnormalities at 48 weeks of treatment. CONCLUSIONS: ENB-0040, an enzyme-replacement therapy, was associated with improved findings on skeletal radiographs and improved pulmonary and physical function in infants and young children with life-threatening hypophosphatasia. (Funded by Enobia Pharma and Shriners Hospitals for Children; ClinicalTrials.gov number, NCT00744042.).

A novel GLRA1 mutation associated with an atypical hyperekplexia phenotype.

Hyperekplexia (MIM #149400) is a rare neurological disorder characterized by an exaggerated startle response, infantile hypertonia and hyperreflexia without spasticity, a hesitant gait that usually improves by 3 years of age, and nocturnal myoclonus. Familial hyperekplexia is usually autosomal dominant resulting from mutations in the inhibitory glycine receptor subunit alpha 1 (GLRA1) gene on chromosome 5q. We identified a 3-generation family with progressively severe phenotypes of hyperekplexia. All affected family members were found to be heterozygous for a novel arginine271proline mutation in GLRA1. Long-term follow-up of the affected members of the third generation, now aged 6 and 7 years, reveals enhanced startle responses and persistent hypertonia of the extremities without clonus or a catch, tight heel cords and abnormal toe-walking gait, and plantar flexor reflexes. The 7-year-old child recently reponded well to a benzodiazepine. Future studies are warranted to examine whether this new missense mutation is solely responsible for this atypical phenotype.

Cost-effectiveness of intrathecal baclofen therapy for the treatment of severe spasticity associated with cerebral palsy.

Spasticity is relatively common among children with cerebral palsy. This condition can be painful, can severely impair a child's ability to perform basic tasks, and can place an enormous emotional and financial burden on the family. Intrathecal baclofen delivered via an implantable pump is an effective treatment option for children unresponsive to oral medication and needing generalized motor control. However, the initial investment for the delivery device and its surgical placement can be a barrier to access. A cost-effectiveness analysis of intrathecal baclofen for adults in the British health care system concluded that intrathecal baclofen offered good value for the money. No similar analysis of intrathecal baclofen has been conducted in the context of the US health care system, and no study has specifically examined cost-effectiveness of intrathecal baclofen in a pediatric population. The aim of this article is to assess the cost-effectiveness of intrathecal baclofen among children with severe spasticity of cerebral origin who have not responded to less invasive treatments such as oral medications relative to alternative medical and surgical therapy. The authors used mathematical modeling and computer simulation to estimate the incremental cost per quality-adjusted life-year for identical cohorts of children treated with intrathecal baclofen or alternative therapy over a 5-year episode of treatment. Data on treatment costs representative of these children were derived from a health insurance claims database that included both commercial and Medicaid data. Utility values used to construct quality-adjusted life-years were obtained from a panel of expert clinicians who used the Health Utilities Index-2 to rate health states associated with the course of treatment. On average, intrathecal baclofen therapy increased the 5-year cost of treatment by $49 000 relative to alternative treatment. However, this was accompanied by an average gain of 1.2 quality-adjusted life-years. The net result was an incremental cost-effectiveness ratio of $42 000 per quality-adjusted life-year, a figure well within the $50 000 to $100 000 range that is widely accepted as offering good value for the money.

Oral pharmacotherapy of childhood movement disorders.

Movement disorders, a common problem in children with neurologic impairment, are receiving increasing clinical attention. The differences in movement disorders between adults and children are striking; presentation is frequently insidious and may be characterized by mild hypotonia. The clinical manifestations of extrapyramidal disorders are profoundly influenced by the age of onset. The conditions reviewed in this article are expressed clinically by the occurrence of abnormalities of movement and posture, often in association with disturbances of muscle tone. This article reviews empiric drug use and recommendations for childhood movement disorders.

Serial casting vs combined intervention with botulinum toxin A and serial casting in the treatment of spastic equinus in children.

PURPOSE: Serial casting has been an effective tool used by physical therapists to increase ankle dorsiflexion range of motion and improve functional gait. The purpose of this retrospective study was to determine whether injection with botulinum toxin type A (BtA) before serial casting vs serial casting alone was associated with any changes in (1) the number of weeks necessary to reach the desired dorsiflexion range of motion and (2) the number of degrees of dorsiflexion range of motion gained per week of casting. METHOD: Data were obtained through review of records maintained on patients undergoing serial casting. Thirty subjects comprised the two groups of 15 patients each. One group had received BtA before serial casting while the other group had received no BtA before serial casting. Data were analyzed using two t tests to determine whether there were significant differences, and the appropriate statistical adjustment (Bonferroni) was applied. RESULTS: Fewer weeks were required to reach the goal of 15 to 20 degrees of ankle dorsiflexion (or plateau) for the group receiving BtA than for the group that did not receive BtA. Results also indicated that the group receiving BtA had a significantly greater increase in range of motion per week than the group that received no BtA. CONCLUSIONS: Using serial casting in conjunction with BtA may achieve range of motion goals in less time than serial casting alone.

Abrupt withdrawal from intrathecal baclofen: recognition and management of a potentially life-threatening syndrome.

OBJECTIVE: To suggest guidelines for the prevention, recognition, and management of a life-threatening syndrome (high fever, altered mental status, profound muscular rigidity that sometimes progressed to fatal rhabdomyolysis) in patients who experience the abrupt withdrawal of intrathecal baclofen (ITB) therapy. DESIGN: Retrospective literature and safety-file review. SETTING: Expert panel drawn from physiatry, neurology, and neurosurgery. PARTICIPANTS: Experienced users of ITB therapy in the pediatric and adult populations in the United States. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: We reviewed literature reports, MedWatch reports to the US Food and Drug Administration, and our own experiences. We critically analyzed patient management and drug therapy in the context of the pharmacology of baclofen and other antispastic agents. RESULTS: An abrupt reduction in gamma-aminobutyric acid(B) (GABA) agonist activity in the central nervous system can cause the ITB withdrawal syndrome, which is clinically and pathophysiologically distinct from autonomic dysreflexia, malignant hyperthermia, and neuroleptic-malignant syndrome. ITB withdrawal evolves over 1 to 3 days, but may become fulminant if not recognized and treated early. The syndrome can be interrupted by the restoration of ITB therapy. However, supportive measures and high-dose benzodiazepine infusion may be life saving in the interval before ITB therapy is resumed. Dantrolene infusion may relieve muscle rigidity but does not reverse the other manifestations of GABAergic agonist withdrawal. CONCLUSIONS: Most episodes of severe ITB withdrawal were preventable. Patients at risk can be identified and educated prospectively and given medication for emergency use. Treatment with GABAergic agonist drugs may prevent potentially fatal sequelae.

Factors Associated with Academic Achievement in Children with Controlled Epilepsy.

Children with epilepsy are at risk for academic underachievement. Multiple etiologies for this academic vulnerability have been suggested by past research including lower self-esteem, inattention, memory inefficiency, and lower socioeconomic status. The present study assessed 65 children (mean age = 10 years, 5 months) with well-controlled epilepsy on the four primary factors, as well as academic achievement and intelligence. A stepwise regression analysis was employed with academic achievement as the dependent variable and measures of self-esteem, attention, memory, and socioeconomic status as independent variables. When intelligence was controlled, attention was the only variable associated with achievement scores. Seizure variables including seizure type and duration of epilepsy were not associated with differences in academic performance. Findings support the importance of measuring attention skills in children with epilepsy and suggest that reduced auditory attention skills may be associated with decreased academic performance in these children.