KIF1A variants are a frequent cause of autosomal dominant hereditary spastic paraplegia.

Variants in the KIF1A gene can cause autosomal recessive spastic paraplegia 30, autosomal recessive hereditary sensory neuropathy, or autosomal (de novo) dominant mental retardation type 9. More recently, variants in KIF1A have also been described in a few cases with autosomal dominant spastic paraplegia. Here, we describe 20 KIF1A variants in 24 patients from a clinical exome sequencing cohort of 347 individuals with a mostly 'pure' spastic paraplegia. In these patients, spastic paraplegia was slowly progressive and mostly pure, but with a highly variable disease onset (0-57 years). Segregation analyses showed a de novo occurrence in seven cases, and a dominant inheritance pattern in 11 families. The motor domain of KIF1A is a hotspot for disease causing variants in autosomal dominant spastic paraplegia, similar to mental retardation type 9 and recessive spastic paraplegia type 30. However, unlike these allelic disorders, dominant spastic paraplegia was also caused by loss-of-function variants outside this domain in six families. Finally, three missense variants were outside the motor domain and need further characterization. In conclusion, KIF1A variants are a frequent cause of autosomal dominant spastic paraplegia in our cohort (6-7%). The identification of KIF1A loss-of-function variants suggests haploinsufficiency as a possible mechanism in autosomal dominant spastic paraplegia.

Medium-dose riboflavin as a prophylactic agent in children with migraine: a preliminary placebo-controlled, randomised, double-blind, cross-over trial.

BACKGROUND: Riboflavin seems to have a promising effect on migraine in adults. The present study examines whether riboflavin has a prophylactic effect on migraine in children. OBJECTIVE: To investigate whether riboflavin in a dosage of 50 mg/day has a prophylactic effect on migraine attacks in young children. SUBJECTS AND METHODS: This randomised, placebo-controlled, double-blind, cross-over trial included 42 children (aged 6-13 years) with migraine of whom 14 children were also suffering from tension-type headache. Following a 4-week baseline period, all children received placebo for 16 weeks then riboflavin for 16 weeks (or vice versa) with a washout period of 4 weeks in between. The primary outcome measure was reduction in mean frequency of migraine attacks and tension-type headache in the last 4 weeks at the end of the riboflavin and placebo phase, compared with the preceding baseline or wash-out period. Secondary outcome measures were mean severity and mean duration of migraine and tension-type headaches in the last 4 weeks at the end of the riboflavin and placebo phase, compared with the preceding baseline or wash-out period. RESULTS: No significant difference in the reduction of mean frequency of migraine attacks in the last month of treatment was found between placebo and riboflavin (P = 0.44). However, a significant difference in reduction of mean frequency of headaches with a tension-type phenotype was found in favour of the riboflavin treatment (P = 0.04). CONCLUSIONS: In this group of children with migraine, there is no evidence that 50 mg riboflavin has a prophylactic effect on migraine attacks. We found some evidence that 50 mg riboflavin may have a prophylactic effect on interval headaches that may correspond to mild migraine attacks or tension-type headache attacks in children with migraine.

Psychopathology in children and adolescents with migraine in clinical studies: a systematic review.

BACKGROUND: In past decades, numerous population- and hospital-based studies have revealed a relationship between migraine or headache and psychopathology in children. OBJECTIVE: To describe and assess all clinical studies on the prevalence and manifestations of psychological functioning and psychiatric comorbidity in children with migraine and to provide recommendations for its diagnosis and treatment. METHODS: A literature search was performed in Medline, Embase, PsycINFO, and the Cochrane Database to identify clinical studies that assessed psychological functioning and/or psychiatric comorbidity in children with migraine. Trial quality was assessed according to a standardized and validated set of criteria. RESULTS: Seven studies met our inclusion criteria. Evidence assessment was performed by using the best-evidence synthesis method of Slavin. On the basis of this method, we found strong evidence that children with migraine in a clinical setting do not exhibit more withdrawn behavior, do not have more thought problems, do not have more social problems, and do not exhibit more delinquent or aggressive behavior than healthy children. Furthermore, there is strong evidence that children with migraine have more somatic complaints and exhibit internalizing behavior which is, given the construct of the outcome measure used, a consequence of the nature of their disease rather than a sign of psychological dysfunctioning. Finally, compared with healthy children, there is limited evidence that children with migraine in a clinical setting are more frequently diagnosed with oppositional defiant disorder, and they are not more frequently diagnosed with attention-deficit/hyperactivity disorder, conduct disorder, dysthymia, or depression. CONCLUSIONS: On the basis of this review, we conclude that children with migraine at referral to a specialist do not exhibit more psychological dysfunctioning and (to a lesser extent) do not exhibit more psychiatric comorbidity compared with healthy controls.

Symptomatic treatment of migraine in children: a systematic review of medication trials.

OBJECTIVE: Treatment of pediatric migraine includes an individually tailored regimen of both nonpharmacologic and pharmacologic measures. The mainstay of symptomatic treatment in children with migraine is intermittent oral or suppository analgesics, but there is no coherent body of evidence on symptomatic treatment of childhood migraine available. The objective of this review is to describe and assess the evidence from randomized and clinical controlled trials concerning the efficacy and tolerability of symptomatic treatment of migraine in children. DESIGN: Systematic review according to the standards of the Cochrane Collaboration. METHODS: Databases were searched from inception to June 2004. Additional reference checking was performed. Two authors independently selected randomized and controlled trials evaluating the effects of symptomatic treatment in children (<18 years old) with migraine, using headache (HA) clinical improvement as an outcome measure. Two authors assessed trial quality independently by using the Delphi list, and data were extracted from the original reports by using standardized forms. Quantitative and qualitative analysis was conducted according to type of intervention. RESULTS: A total of 10 trials were included in this review, of which 6 studies were considered to be of high quality. The number of included participants in each trial ranged from 14 to 653, with a total of 1575 patients included in this review. Mean dropout rate was 19.8% (range: 0-39.1%), and the mean age of participants was 11.7 +/- 2.2 years (range: 4-18 years). All studies used HA diaries to assess outcomes. In most studies, a measure of clinical improvement was calculated by using these diaries. Improvement often was regarded as being clinically relevant when the patients' HA declined by > or =50%. Regarding oral analgesic treatment, the effectiveness of acetaminophen, ibuprofen, and nimesulide were evaluated. When compared with placebo, acetaminophen (relative risk [RR]: 1.5; 95% confidence interval [CI]: 1.0-2.1) and ibuprofen (pooled RR: 1.5; 95% CI: 1.2-1.9) significantly reduced HAs. We conclude that there is moderate evidence that both acetaminophen and ibuprofen are more effective in reduction of symptoms 1 and 2 hours after intake than placebo with minor adverse effects. No clear differences in effect were found between acetaminophen and ibuprofen or nimesulide. Regarding the nonanalgesic interventions, nasal-spray sumatriptan, oral sumatriptan, oral rizatriptan, oral dihydroergotamine, intravenous prochlorperazine, and ketorolac were evaluated. When compared with placebo, nasal-spray sumatriptan (pooled RR: 1.4; 95% CI: 1.2-1.7) seemed to significantly reduce HAs. We conclude that there is moderate evidence that nasal-spray sumatriptan is more effective in reduction of symptoms than placebo but with significantly more adverse events. No differences in effect were found between oral triptans and placebo. All medications were well tolerated, but significantly more adverse events were reported for nasal-spray sumatriptan compared with placebo. We also conclude that there is moderate evidence that intravenous prochlorperazine is more effective than intravenous ketorolac in the reduction of symptoms 1 hour after intake. No differences in effect were found between oral dihydroergotamine and placebo. CONCLUSIONS: Acetaminophen, ibuprofen, and nasal-spray sumatriptan are all effective symptomatic pharmacologic treatments for episodes of migraine in children. The new frontier for symptomatic treatment is likely to be the development of triptan agents for use in children. Most treatments have only been evaluated in 1 or 2 studies, which limits the generalizability of the findings. We strongly recommend performing a large, high-quality randomized, controlled trial evaluating different symptomatic medications compared with each other or to placebo treatment. Favorable high-quality studies should be performed and reported according to the CONSORT statement. Clinical improvement of HA should be used as the primary outcome measure, but quality of life, days missed at school, and satisfaction of child or parents should also be used as an outcome measure in future studies.