Efficacy and safety of methylphenidate on attention deficit hyperactivity disorder in children with Down syndrome.

BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common co-morbidity that affects up to 44% of children with Down syndrome (DS). There is a need for reliable, good quality research on the use of methylphenidate within this population. The objective of this study is to report our experience regarding the management of ADHD in these children using methylphenidate. METHODS: This study is a retrospective observation of 21 children with DS, followed at Jérôme Lejeune Institute between 2000 and 2018. The diagnosis of ADHD was made using the Diagnostic and Statistical Manual of Mental Disorders criteria. Efficacy was measured as response or non-response on two main symptoms: attention/concentration and hyperactivity/impulsivity. Safety was evaluated by the presence or absence of side effects. RESULTS: Sixteen out of the 21 children (76%) showed improvement with methylphenidate. The average age of treatment onset in responding children was 8 years and 10 months versus 6 years and 3 months in non-responders (P = 0.05). Average dose/weight was significantly different in responders and non-responders (0.82 vs. 0.54 mg/kg/day, respectively; P = 0.03). Twelve children out of 21 (57%) experienced side effects; only three experienced side effects severe enough to require treatment interruption. Most common side effects were loss of appetite and difficulties in falling asleep. CONCLUSION: Methylphenidate was effective and safe in treating ADHD in 76% of cases in children with DS, with few serious side effects to report. Early diagnosis of ADHD is important to improve the quality of life, learning, inclusion and socialisation of children with DS.

Feeding problems and gastrointestinal diseases in Down syndrome.

BACKGROUND AND METHOD: Feeding problems and gastrointestinal disorders are the most common anomalies in people with Down syndrome (DS) and have a significant impact on their daily life. This study lists the various anomalies on the basis of 504 references selected from a PubMed search in October 2018. RESULTS: The anomalies are grouped into three categories: anatomical anomalies: duodenal atresia and stenosis (3.9%), duodenal web and annular pancreas; aberrant right subclavian artery (12% of children with DS with cardiac anomaly); Hirschsprung's disease (2.76%); anorectal malformation (1.16%); congenital vascular malformations of the liver; orofacial cleft, bifid uvula (4.63%), and submucous orofacial cleft; esophageal atresia (0.5-0.9%); pyloric stenosis (0.3%); diaphragmatic hernia; malrotation of small intestine or duodenum inversum; omphalocele, gastroschisis or anomalies of the median line, anomalies of the umbilical vein; biological, immunological, and infectious anomalies: neonatal cholestasis (3.9%); neonatal hepatic fibrosis; Helicobacter pylori infection (75.8% in institutionalized children with DS, between 29.2 and 19.5% in non-institutionalized); non-alcoholic fatty liver disease (NAFLD; 82% in obese and 45% in non-obese); biliary lithiasis (6.9% under 3 years); celiac disease (6.,6%); geographical tongue (4%); hepatitis B virus sensitivity; autoimmune hepatitis and cholangitis; Crohn's disease, inflammatory bowel disease (IBD); pancreatitis; vitamin D deficiency (45.2% in Italy); functional disorders: suction, swallowing and chewing disorders (13 of 19 children with DS under 4 years); gastroesophageal reflux (47% in children with sleep apnea); achalasia (0,5% in adults); obesity (51.6% of males and 40.0% of females in Ireland) and overweight (32.0% and 14.8%); constipation (19.0%). Based on their practice, the authors insist on the following points: malformations are sometimes detected late (chronic vomiting after the introduction of food pieces, resistant constipation despite appropriate measures); prescription of preventive doses of vitamin D is advised; jaundice in a baby with DS may be retentional; in the event of transient leukemoid reaction it is vital to monitor liver function; the patient with geographic tongue must be reassured; for celiac serology there is no consensus on the staring age and the frequency, we propose every year from the age of 2; we advise to test people with DS for H. pylori infection if they are attending specialized institutions; abdominal ultrasounds must be systematic during the first months of life; detection of NAFLD is recommended; people with DS must be vaccinated against hepatitis B; breastfeeding is possible with maternal support; it is important to start speech therapy very early; feeding difficulties are often overlooked by the family and educators; gastroesophageal reflux is often pathological; preventing obesity must start from birth using body mass index for the general population; it is necessary to do everything for their meals to be joyful.

Update on Kleefstra Syndrome.

Kleefstra syndrome is characterized by the core phenotype of developmental delay/intellectual disability, (childhood) hypotonia and distinct facial features. The syndrome can be either caused by a microdeletion in chromosomal region 9q34.3 or by a mutation in the euchromatin histone methyltransferase 1 (EHMT1) gene. Since the early 1990s, 85 patients have been described, of which the majority had a 9q34.3 microdeletion (>85%). So far, no clear genotype-phenotype correlation could be observed by studying the clinical and molecular features of both 9q34.3 microdeletion patients and patients with an intragenic EHMT1 mutation. Thus, to further expand the genotypic and phenotypic knowledge about the syndrome, we here report 29 newly diagnosed patients, including 16 patients with a 9q34.3 microdeletion and 13 patients with an EHMT1 mutation, and review previous literature. The present findings are comparable to previous reports. In addition to our former findings and recommendations, we suggest cardiac screening during follow-up, because of the possible occurrence of cardiac arrhythmias. In addition, clinicians and caretakers should be aware of the regressive behavioral phenotype that might develop at adolescent/adult age and seems to have no clear neurological substrate, but is rather a so far unexplained neuropsychiatric feature.

[One carbon metabolism and trisomy 21: analysis of the genetic polymorphism]. / Métabolisme des substrats monocarbonés et trisomie 21: analyse de l'impact des polymorphismes génétiques.

Trisomy 21 is the most common chromosome abnormality characterized by the presence of three copies of chromosome 21 in the genome. The clinical disorder attributed to trisomy 21 is Down syndrome. Patients with Down syndrome are heterogeneous in their phenotypic expression. Due to the location of the cystathionine b-synthase gene on chromosome 21, and its involvement in one carbon metabolism, homocysteine levels have been found to be decreased in children with Down syndrome. The study of the regulation of one carbon metabolism in Down syndrome becomes important in light of possible normalization of the metabolic imbalance and the detection of increased sensitivity to therapeutic interventions. Thus, the importance of evaluating single nucleotide polymorphisms in genes involved in one carbon metabolism need to be addressed in individuals with trisomy 21. This review offers an analysis of the impact of these polymorphisms in Down syndrome and their possible implications for phenotypic heterogeneity.

[Variation of amino acids in relation to age in Down syndrome subjects]. / Variation des acides aminés en fonction de l'âge chez des sujets trisomiques 21.

BACKGROUND: A preliminary study of plasma and urinary amino acid concentration in Down's syndrome subjects had shown some impairments. PATIENTS AND METHODS: A comparative study of the variations of amino acid concentration with age in Down's syndrome subjects aged 0 to 60 years and in control subjects aged 0 to 94 years was made in order to determine whether these impairments could be explained by generalized premature aging, or by a specific gene dosage effect. RESULTS: Two major changes (P < 0.001) were found in Down's syndrome: a decrease in plasma concentration of serine at any age, which could be due to a dosage effect of cytathionine-beta-synthase, and an increase in plasma lysine concentration in patients above 10 year's old, probably due to premature aging. Other minor changes were also present in plasma and urine, also possibly explained by premature aging. CONCLUSIONS: Other studies are necessary to evaluate possible consequences of such changes in the amino acid profiles.

Excessive glutamine sensitivity in Alzheimer's disease and Down syndrome lymphocytes.

In addition to clinical and neuropathological similarities between Alzheimer's disease and Down syndrome there are genetic and biochemical data which suggest common disease mechanism. Using an in vitro assay examining variations of the mitotic index in the presence or absence of various inhibitors or metabolites of purine and/or pyrimidine synthesis, we studied 19 Alzheimer disease patients and 16 patients with both Down syndrome and Alzheimer type dementia. A highly significant decrease in mitotic index in the presence of exogenous glutamine was noted in patients presenting an Alzheimer type dementia with or without associated Down syndrome. These findings suggest that glutamine sensitivity or some dysregulation of the glutamine/glutamate pathway may play a role in the pathogenesis of Alzheimer's disease. If these findings are confirmed, they would have important implications in the development of preventive strategies.

[Amino acids and trisomy 21]. / Acides aminés et trisomie 21.

The relative concentrations of plasmatic and urinary amino acids were analysed in 79 trisomic-21 patients, 322 mentally retarded non-trisomic patients, and 206 controls. No true amino acidopathy was found in 21-trisomy, but in plasma a deficit of serine and an excess of cysteine and lysine are highly significant. Excesses of cysteine, methionine, tyrosine, and methyl-histidine are also typical in urine. The increased activity of superoxide-dismutase, cystathionine-beta-synthase, and purine synthesis enzymes, together with the sensitivity to methotrexate, atropine, and dysthyroidism, are in accordance with this shift of equilibrium. A nutritional compensation seems worth investigating.