Ann Reynolds

Cognitive Profile of Fragile X Premutation Carriers With and Without Fragile X-Associated Tremor/Ataxia Syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS) develops in a subset of fragile X premutation carriers and involves gait ataxia, action tremor, Parkinsonism, peripheral neuropathy, autonomic disorders, and cognitive impairment. The study was designed to define the nature of cognitive deficits affecting male premutation carriers with and without FXTAS. A sample of 109 men underwent motor, cognitive, genetic, and neurologic testing, as well as brain magnetic resonance imaging. Subjects were classified into 3 groups: (a) asymptomatic premutation carriers, (b) premutation carriers with FXTAS, and (c) normal controls. Men with FXTAS performed worse than controls on mental status, intelligence, executive cognitive functioning (ECF), working memory, remote recall of information, declarative learning and memory, information processing speed, and temporal sequencing, as well as 1 measure of visuospatial functioning. Language and verbal comprehension were spared. Asymptomatic carriers performed worse than controls on ECF and declarative learning and memory. This comprehensive examination of cognitive impairment in male premutation carriers suggests that FXTAS involves substantial executive impairment and diffuse deficits in other cognitive functions. Longitudinal research currently underway will provide insight into the progression of the disorder.

FMR1 CGG repeat length predicts motor dysfunction in premutation carriers

Background: Fragile X–associated tremor/ataxia syndrome (FXTAS) is a recently described, underrecognized neurodegenerative disorder of aging fragile X mental retardation 1 (FMR1) premutation carriers, particularly men. Core motor features are action tremor, gait ataxia, and parkinsonism. Carriers have expanded CGG repeats (55 to 200); larger expansions cause fragile X syndrome, the most common heritable cause of mental retardation and autism. This study determines whether CGG repeat length correlates with severity and type of motor dysfunction in premutation carriers. Methods: Persons aged ≥50 years with a family history of fragile X syndrome underwent structured videotaping. Movement disorder neurologists, blinded to carrier status, scored the tapes using modified standardized rating scales. CGG repeat length analyses for women incorporated the activation ratio, which measures the percentage of normal active chromosome X alleles. Results: Male carriers (n = 54) had significantly worse total motor scores, especially in tremor and ataxia, than age-matched male noncarriers (n = 51). There was a trend toward a difference between women carriers (n = 82) and noncarriers (n = 39). In men, increasing CGG repeat correlated with greater impairment in all motor signs. In women, when activation ratio was considered, increasing CGG correlated with greater ataxia. Conclusions: CGG repeat size is significantly associated with overall motor impairment in premutation carriers. Whereas this association is most pronounced for men and covers overall motor impairment—tremor, ataxia, and parkinsonism—the association exists for ataxia among women carriers. This is the first report of a significant correlation between the premutation status and a motor feature of fragile X–associated tremor/ataxia syndrome in women. GLOSSARY: AR = activation ratio; FXTAS = fragile X-associated tremor/ataxia syndrome; MCP = middle cerebellar peduncle; mRNA = messenger RNA.

Progression of tremor and ataxia in male carriers of the FMR1 premutation

Premutation alleles of the fragile X mental retardation 1 (FMR1) gene give rise to a late‐onset movement disorder, fragile X‐associated tremor/ataxia syndrome (FXTAS), characterized by progressive intention tremor and gait ataxia, with associated dementia and global brain atrophy. The natural history of FXTAS is largely unknown. To address this issue, a family‐based, retrospective, longitudinal study was conducted with a cohort of 55 male premutation carriers. Analysis of the progression of the major motor signs of FXTAS, tremor and ataxia, shows that tremor usually occurs first, with median onset at ∼60 years of age. From the onset of the initial motor sign, median delay of onset of ataxia was 2 years; onset of falls, 6 years; dependence on a walking aid, 15 years; and death, 21 years. Preliminary data on life expectancy are variable, with a range from 5 to 25 years.

A New Look at XXYY Syndrome : Medical and Psychological Features

XXYY syndrome occurs in approximately 1:18,000–1:40,000 males. Although the physical phenotype is similar to 47,XXY (tall stature, hypergonadotropic hypogonadism, and infertility), XXYY is associated with additional medical problems and more significant neurodevelopmental and psychological features. We report on the results of a cross‐sectional, multi‐center study of 95 males age 1–55 with XXYY syndrome (mean age 14.9 years), describing diagnosis, physical features, medical problems, medications, and psychological features stratified by age groups. The mean age of diagnosis was 7.7 years. Developmental delays and behavioral problems were the most common primary indication for genetic testing (68.4%). Physical and facial features varied with age, although hypertelorism, clinodactyly, pes planus, and dental problems were common across all age groups. Tall stature was present in adolescents and adults, with a mean adult stature of 192.4 cm (SD 7.5; n = 22). Common medical problems included allergies and asthma (>50%), congenital heart defects (19.4%), radioulnar synostosis (17.2%), inguinal hernia and/or cryptorchidism (16.1%), and seizures (15%). Medical features in adulthood included hypogonadism (100%), DVT (18.2%), intention tremor (71%) and type II diabetes (18.2%). Brain MRI (n = 35) showed white matter abnormalities in 45.7% of patients and enlarged ventricles in 22.8%. Neurodevelopmental and psychological difficulties were a significant component of the behavioral phenotype, with developmental delays and learning disabilities universal but variable in severity. Twenty‐six percent had full‐scale IQs in the range of intellectual disability (MR), and adaptive functioning was significantly impacted with 68% with adaptive composite scores <70. Rates of neurodevelopmental disorders, including ADHD (72.2%), autism spectrum disorders (28.3%), mood disorders (46.8%), and tic disorders (18.9%), were elevated with 55.9% on psychopharmacologic medication overall. Recommendations for evaluation and treatment are summarized.

Breastfeeding and brain development.

Although biochemical evidence seems to support the fact that more DHA is incorporated into the brain of breastfed infants compared with formula-fed infants, whether the levels of DHA in the brain are clinically significant is unclear. Because randomized trials cannot be done, this issue is difficult to study. The effects of breastfeeding on developmental outcome in term infants seems to be small or insignificant. For otherwise healthy children the potential differences are not clinically relevant; however, these small differences distributed over an entire population might have a significant effect on society. Although significant methodologic concerns exist, the effects of breastfeeding on preterm infants may be greater than those for term infants. Extremely low birth weight, premature infants (< 750-1000 g) have been found to have IQs that are 13 points lower than term controls and a 50% to 60% risk for requiring special-education services when they are in school. In these infants, small improvements in IQ and neurologic function could have a much greater effect. Further study of neurodevelopmental outcome in premature infants fed breast milk compared with those fed preterm formula are indicated. This information should not change the practice of encouraging breastfeeding of term and preterm infants because other advantages to breastfeeding exist.

Use of Psychotropic Medication in Children and Adolescents With Autism Spectrum Disorders

OBJECTIVES: The goal of this study was to examine rates of psychotropic medication use and identify associated child and family characteristics among children and adolescents with autism spectrum disorder (ASD) enrolled in an autism registry maintained by the Autism Treatment Network (ATN). METHODS: The sample, derived from the ATN registry, consists of 2853 children aged 2 to 17 years with diagnoses of ASD supported by Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, and the Autism Diagnostic Observation Schedule with available data on medication use. As part of initial enrollment in the registry, parents completed questionnaires on current psychotropic medication use, psychiatric and medical conditions, and demographics. RESULTS: Of the 2853 children, 763 (27%) were taking ≥1 psychotropic medication; 15% were prescribed 1 medication, 7.4% received 2 medications, and 4.5% received ≥3. Among children aged 3 to 5 years, 11% were taking ≥1 psychotropic medication; among 6-to 11-year-old children, 46%; and 66% of adolescents aged 12 to 17 years were taking at ≥1 psychotropic medication. A parent report of comorbid diagnosis of attention-deficit/hyperactivity disorder, bipolar disorder, obsessive-compulsive disorder, depression, or anxiety was associated with a high rate of use, with 80% receiving ≥1 psychotropic medication. Only 15% of children with no comorbid psychiatric disorder were taking psychotropic medication. Psychotropic medication use was also related to sleep and gastrointestinal problems. CONCLUSIONS: The prescription of psychotropic medications in this registry sample is highly related to comorbid psychiatric disorder. Other factors associated with use include medical comorbidities, race, ethnicity, and older age. Pediatrics 2012;130:S69—S76.

Nutrient Intake From Food in Children With Autism

OBJECTIVE The impact of abnormal feeding behaviors reported for children with autism spectrum disorders (ASDs) on their nutritional status is unknown. We compared nutrient intake from food consumed by children with and without ASD and examined nutrient deficiency and excess. METHODS Prospective 3-day food records and BMI for children (2–11 years) with ASD participating in the Autism Treatment Network (Arkansas, Cincinnati, Colorado, Pittsburgh, and Rochester) were compared with both the National Health and Nutrition Examination Survey data and a matched subset based on age, gender, family income, and race/ethnicity (N = 252 analyzed food records). RESULTS Children with ASD and matched controls consumed similar amounts of nutrients from food. Only children with ASD aged 4 to 8 years consumed significantly less energy, vitamins A and C, and the mineral Zn; and those 9 to 11 years consumed less phosphorous. A greater percentage of children with ASD met recommendations for vitamins K and E. Few children in either group met the recommended intakes for fiber, choline, calcium, vitamin D, vitamin K, and potassium. Specific age groups consumed excessive amounts of sodium, folate, manganese, zinc, vitamin A (retinol), selenium, and copper. No differences were observed in nutritional sufficiency of children given restricted diets. Children aged 2 to 5 years with ASD had more overweight and obesity, and children 5 to 11 years had more underweight. CONCLUSIONS Children with ASD, like other children in America, consume less than the recommended amounts of certain nutrients from food. Primary care for all children should include nutritional surveillance and attention to BMI.

Sleep and Autism Spectrum Disorders

Sleep disorders are common in children with autism spectrum disorders and have a significant effect on daytime function and parental stress. The cornerstone of treatment is to establish the cause of the sleep concern, which is often multifactorial. Identifying and treating sleep disorders may result not only in more consolidated sleep, more rapid time to fall asleep, and avoidance of night waking but also favorably affect daytime behavior and parental stress. Targeting effective treatment strategies is dependent on understanding the underlying causes of sleep problems in children with Autism spectrum disorders, therefore further research is paramount.

The primary cognitive deficit among males with fragile X-associated tremor/ataxia syndrome (FXTAS) is a dysexecutive syndrome

Fragile X-associated tremor/ataxia syndrome (FXTAS) is a neurodegenerative disorder associated with a premutation trinucleotide repeat expansion in the fragile X mental retardation 1 gene. Symptoms include gait ataxia, action tremor, and cognitive impairment. The objectives of the study were to clarify the nature of the dysexecutive syndrome observed in FXTAS and to assess the contribution of executive impairment to deficits in nonexecutive cognitive functions. Compared to controls, men with FXTAS demonstrated significant executive impairment, which was found to mediate group differences in most other cognitive abilities. Asymptomatic premutation carriers performed similarly to controls on all but two measures of executive functioning. These findings suggest that the impairment of nonexecutive cognitive skills in FXTAS is in large part secondary to executive dysfunction.

Complementary and Alternative Medicine Use in a Large Pediatric Autism Sample

BACKGROUND AND OBJECTIVE Children and adolescents with autism spectrum disorder (ASD) often use complementary and alternative medicine (CAM), usually along with other medical care. This study aimed to determine associations of ASD diagnostic category, co-existing conditions, and use of medications with use of CAM. METHODS We used the Autism Speaks Autism Treatment Network patient registry, which collects information on CAM use, medical conditions, and psychotropic medication at enrollment. CAM was categorized as special diets versus “other” CAM; ASD was defined as autism, pervasive developmental disorder (PDD), or Asperger’s. Gastrointestinal symptoms, seizure disorders, sleep problems, and medication use were determined from parent report. Child Behavior Checklist (CBCL) scores were used to measure behavioral symptoms. Logistic regression was used to determine associations of diagnostic category, other medical conditions, and medication use with CAM treatments, controlling for demographic characteristics. RESULTS Of 3413 subjects in the registry as of April 2011, 3173 had complete data on CAM use: 896 (28%) reported any use; 548 (17%), special diets; and 643 (20%), other CAM. Higher rates of CAM use were associated with gastrointestinal symptoms (odds ratio [OR] = 1.88), seizures (OR = 1.58), and CBCL total score >70 (OR = 1.29). Children with PDD (OR = 0.62), Asperger’s (OR = 0.66), or using medications (0.69) had lower rates. CONCLUSIONS Children with ASD use more CAM when they have co-existing gastrointestinal symptoms, seizure disorders, and behavior problems. This study suggests the importance of asking about CAM use in children with ASD, especially those with complex symptoms.