Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies.

Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies.

Acute Onset Esotropia From Excessive Smartphone Use in a Teenager.

Acute acquired comitant esotropia secondary to smart-phone use is a newly described phenomenon. This case report describes a boy with acute acquired comitant esotropia due to prolonged smartphone use who had improvement in binocular function after cessation of near work for several weeks. [J Pediatr Ophthalmol Strabismus. 2018;55:e42-e44.].

The economic burden of spinal muscular atrophy.

AIM: To evaluate the economic burden of spinal muscular atrophy (SMA). MATERIALS AND METHODS: This study used Department of Defense Military Healthcare System (MHS) data from 2003-2012. Healthcare costs were determined for patients with at least one inpatient or three outpatient claims with a diagnosis of SMA before 18 years of age and who had ≥ 6 months of data after first SMA diagnosis or expired within 6 months of initial diagnosis. A comparator cohort was selected using a 3:1 match based on age and gender. RESULTS: A total of 239 individuals with SMA diagnosis met the inclusion criteria along with 717 matched comparator patients. More patients with SMA had hospitalizations (69.5%) compared to the comparator cohort (17.2%, p < 0.001). Median total expenditures across all years of data for patients with SMA were $83 652 (25-75th percentile = $29 620-228 754) vs the comparator group of $4329 (25-75(th) percentile = $1229-10 062 (p < 0.001)) over an average (SD) of 6.9 ± 3.6 years. The annualized mean costs of total healthcare expenditures were significantly higher for the SMA cases than the comparison cohort, $47 862 ± 88 607 compared to $1861 ± 6374, respectively (p < 0.001). The sub-group of patients with early diagnosis (n = 45) had 4.3 ± 2.9 years of observation with a median cost of $167 921 ($53 349-678 412). Mean age (SD) at first observed SMA diagnosis was 7.5 ± 6.4 years. Mean (SD) duration of follow-up after initial SMA diagnosis was 4.8 ± 3.3 years, with a median post-diagnosis cost of $60 213 ($18 229-192 559). The major costs for all patients were outpatient visits [median = $53 152 ($23 902-136 150)], followed by inpatient costs [median = $11 258 ($0-51 987)] and total prescription costs [median = $3167 ($943-13 283)]. LIMITATIONS: The analysis is limited to the data available and may under-estimate the total cost of SMA. CONCLUSIONS: Individuals with SMA have a high degree of morbidity, particularly those diagnosed during infancy. SMA patients have significant medical expenditures and high utilization of healthcare services.

Children's ibuprofen suspension for the acute treatment of pediatric migraine.

OBJECTIVE: To compare the efficacy of a single over-the-counter dose (7.5 mg/kg, p.o.) of children's ibuprofen suspension vs. placebo for the acute treatment of pediatric migraine. BACKGROUND: Migraine occurs in 4% of young children. There is a paucity of controlled clinical research in the treatment of childhood migraine and there are currently no approved drugs in the USA for treatment of migraine in children < or = 12 years of age. The purpose of this study is to assess the efficacy and tolerability of a single OTC dose of ibuprofen suspension for the acute treatment of childhood migraine. METHODS: Prospective, double-blind, placebo-controlled, parallel group, randomized study of children 6-12 yrs with migraine (I.H.S.-R 1997) treating 1 attack with a 7.5 mg/kg liq. ibuprofen vs matching placebo. Efficacy measures: (1). Headache severity based upon a 4 pt scale (severe, mod., mild, no headache) at 30, 60, 90, 120, 180 and 240 minutes post dose, and (2). nausea, vomiting, and photo/phonophobia at 120 min. The 1 degrees endpoint was cumulative % of responders (severe or mod. headache reduced to mild or none) by 120 minutes. Secondary endpoints were headache recurrence within 4-24 hours and need for rescue medicines within 4 hours. RESULTS: 138 enrolled; 84 treated/completed diary. 45 active agent, 39 placebo. The 2 groups were comparable (active: placebo) - Ages: 9: 9.1, gender boy/girl - 1.25: 1.6, and diagnosis: migraine w/o aura - 86%: 79%. Concomitant use of prophylactic Rx: 24%: 10% (Table 3). Nausea was eliminated in 60% of the ibuprofen treated patients and 39% of the placebo group (p<0.001). Vomiting, photophobia and phonophobia had marginal, but not statistically significant, decreases at 2 hours. A striking gender difference was noted (Table 4): No AE's were reported. CONCLUSION: Children's ibuprofen suspension at an OTC dose of 7.5 mg/kg is an effective and well-tolerated agent for pain relief in the acute treatment of childhood migraine, particularly in boys. There is a striking difference in gender response rates and placebo responder rates between girls and boys. The boys responded at a statistically significant rate, and girls failed to do so because of a very high placebo responder rate. Multi-center trials are recommended.