1-sleep habits; 2-Ataxia; 3-child abuse and neglect; 4- Fabry disease; 5- congenital myopathies
Several researches have demonstrated that non-sufficient sleep in childhood is associated with immediate and long-term adverse consequences for mental and physical health. A questionnaire study investigated sleep habits of a large cohort of Italian children between 1 and 14 years to assess their relationship with evening activities performed before bed time [
127]. Younger children slept longer than the older ones. The mean sleep duration was 11.5 h in 1 to 3 years old children vs 9.0 h in 10 to 14 years old but only 66.9% of them got sufficient sleep as recommended by National Sleep Foundation [
128]. The use of display devices before sleeping was a significant predictors of shorter sleep duration. Similarly, having TV in the bedroom, being only child, bottle use habit and a history of sleep disorders during the first year of life negatively influenced optimal sleep conditions. These data agree with the literature data worldwide of the last decade. Tamura and colleagues [
129] found a higher incidence of insomnia and depression and a shorter sleep duration in adolescent using mobile phone for 5 h or more per day. Females had a longer use of mobile phone than males. In particular, hours spent using a mobile phone for social networking sites and online chat were linked with depression, while internet searching and playing video games were not.
In 2334 Canadian children [
130] a longer sleep duration was associated with frequent reading a book in the bedroom and absence of electronic devices, on the contrary use an electronic device before to sleep was associated with shorter sleep duration and shorter total time in bed. Children with a frequent use of computer and TV during the hour before sleep had 20% odds of being overweight and double odds of being obese. Results were similar for cell phones use. Surprisingly, children having a TV or a video game in their bedroom were at risk of overweight and obesity even if they did not use them before sleeping. A study conducted in USA among low-income preschoolers found an inverse relationship between sleep duration and body mass index (BMI) [
131]. Future studies investigating the association between sleep duration, electronic devices use, and BMI are needed to clarify this relationship and the risk of overweight and obesity particularly in high-risk population.
Ataxia is a manifestation of a multitude of disease processes, and an underlying etiology needs to be investigated. Detecting ataxia can be challenging specially in early childhood but simple signs and maneuvers can help to recognize ataxia. In a recent review, Pavone and colleagues [
132] provided a general approach to assessing and managing the patient with ataxia, they also reported the background and common etiologies of ataxia. Unsteadiness of gait with loss of balance is the more common symptom in younger children. Older children often feel insecure and have to hold onto the wall and walk with feet apart. In children over 3 years typical maneuvers such as finger to finger or finger to nose, and rapid alternating hand movements can be performed to explore coordination, while dysmetria can be tested through heel-knee test. Children with ataxia tend to fall down with closed eyes (Romberg sign positive) and cannot hold a glass of water without letting the water fall from the glass. They suggest different ways to classify ataxias but conclude that, in children, the most useful considers time trend. Ataxia may be distinguished as being acute, intermittent and recurrent, chronic-non-progressive and chronic-progressive. The most common etiologies of acute ataxia in children are excessive drug ingestion, drug intoxications and post-infectious cerebellitis, while basilar migraine is the most common cause of intermittent ataxia. But ataxia can also be a sign of rare and more complex diseases as hereditary ataxias. The most well-known of the inherited ataxias includes ataxia-telangiectasia (AT), a rare, neurodegenerative, multiorgan, autosomal recessive disorder causing severe disability. Because of his rarity, the diagnosis of AT is often delayed but it can be made earlier with serum alpha feto-protein (AFP) measurement, a readily available and inexpensive test for all toddlers and children with undiagnosed chronic or progressive ataxia [
133]. Children with AT suffer from increased mortality because of lymphoreticular malignancy, infections of the respiratory system, and various complications. The gene mutated in AT, ATM (ataxia telangiectasia mutated) gene, encodes a large protein kinase. The nature of the immune deficiency is highly variable due to a plethora of mutations of the ATM gene. Some children have a variant AT in which a residual kinase activity leading a milder clinical phenotype, with different immunoglobulin patterns and a longer survival compared to classical AT patients. Life expectancy seems to correlate to some immunoglobulin pattern alterations (IgG2 deficiency or hyper IgM phenotype with hypogammaglobulinemia) [
134].
In recent decades, the concept of child abuse and neglect has evolved [
135]. Children of the new era are increasingly stressed because of changes in living conditions, modern family types, loss of a parent or increasing expectations from parents, teachers or other family members. Increasingly large numbers of children and adolescents have been forced to migrate across the world for several reasons. Mental health of these children is of particular concern because of their experiences. The exposure to organized violence and threats arising from religious, cultural, and political differences, or territorial disputes make them vulnerable to several and cumulative risks to their physical, emotional, and social development. Another class at risk are children in long-term foster care. Several evidences show that children in care have significant developmental, behavioral, and emotional problems. Parental divorce/separation is among the most commonly endorsed adverse childhood events and is another highly prevalent risk factor associated with high rates of mental health problems for youth and increased later risk of alcohol dependence across adolescence and early adulthood [
136].
Soares and colleagues [
137] conducted a comparative study to examine the association between parental divorce during childhood and cardiometabolic risk factors in youth, using data from 2 cohort studies in contrasting contexts (the United Kingdom and Brazil). In both cohorts, cigarette daily smoking was more frequent among adolescents whose parents separated before age 18 years. There was no interaction between age at parental separation and parental relationship conflict and cardiometabolic risk factors. A higher risk of harmful alcohol use was seen in Brazilian cohort but not in English one. Several studies of child maltreatment and sexual risk behavior have shown that males and females who experienced any kind of sexual abuse had significantly increased odds of engagement in risky sexual behaviors, but a recent study revealed that other forms of maltreatment can increase risky behaviors. Thompson and colleagues [
138] showed that maltreated youths continue to be at high risk for engaging in behaviors that may start a trajectory of problematic sexual behaviors. Clinical and prevention programs should target adolescents with a history of maltreatment and pediatric clinicians have a responsibility to screen at-risk youth for maltreatment experiences. A recent review [
139] focused on possible means to screen for child physical, sexual, and psychological abuse and neglect. One screening tools for physical abuse, called the “Escape Form” was applicable to children of any age. Limit of this tool is the use only in emergency situations. Only one screening instrument was found for sexual abuse but it was not approved by the International Association of Forensic Nurses and no screening tool was found to identify psychological abuse and neglect in children. These findings show that further efforts are needed to develop an effective instrument that can identify and prevent child maltreatment and improving child welfare services.
Fabry Disease (FD) is an X-linked multisystemic, lysosomal storage disorder caused by deficiency of α-galactosidase A activity, with consequent accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids, such as globotriaosylsphingosine (lyso-Gb3) in lysosomes. The main complications of FD are more prominent after the age of 30 when kidney, heart and/or cerebrovascular disorders appear. Regarding cardiac involvement, deposits of neutral glycosphingolipids within cardiocytes lead to myocyte hypertrophy and fibrosis causing conduction abnormalities, left ventricular hypertrophy (LVH) or valvular fibrosis. Patients with manifestations limited to the heart have been reported as a disease variation. Csányi et al. [
140] have found a novel Ile239Met mutation in α-galactosidase A gene in a family with a predominant cardiac phenotype of Fabry disease. In this family, 6 individuals carried the Ile239Met mutation of whom 3 members manifested the cardiac phenotype of hypertrophic cardiomyopathy and 2 other family members showed LVH. Interestingly, 4 of the 5 with cardiac involvement were female individuals. This finding is unusual for cardiac FD since the disease shows X linked inheritance.
Wilson et al. [
141] analyzed electrocardiographic and clinical findings in pediatric FD patients. The most common arrhythmia was sinus bradycardia (23%), followed by ectopic atrial rhythm (12%) and premature atrial contraction (8%). No episodes of nonsustained ventricular tachycardia, supra ventricular or ventricular tachycardia, atrial fibrillation and no PR or QTc intervals abnormalities were found. Only 1 female developed a first-degree atrioventricular block during follow-up. Chest pain (35%) and palpitations (23%) were the most common symptoms. Echocardiography detected aortic root dilation in 3 patients, one of them also had concurrent mild aortic insufficiency. These findings show that cardiological involvement in Fabry disease at the beginning is limited and this results in clinical symptoms, abnormalities of conduction and structure largely heterogeneous. In cardiac involvement in a Fabry’s patient, enzyme replacement therapy (ERT) should be started before myocardial fibrosis has developed to achieve long term improvement. Many efforts are needed in order to identify early cardiac alterations to increases the chances of patients to receive a proper therapy and suggest the best age for ERT onset. A recent study suggests that blood LysoGb3 concentrations measurement could aid to define a threshold concentration for new preventive and therapeutic approaches [
142].
After the diagnosis of FD in a 11 years old child, the authors detected the same disease in his little brother, 14 years younger, during neonatal period. The younger brother underwent LysoGb3 analysis at 2 days of life. Blood LysoGb3 concentration obtained from the asymptomatic second-born were compared with serum levels from the symptomatic first-born: there was a 5-fold increase from the neonatal period to childhood; moreover, at five months of age the concentration of LysoGb3 reached 40% of the value observed in the symptomatic phase moreover. They also noted that during neonatal period the value was 15 times higher than children without FD. These findings have demonstrated the key role of LysoGb3 as potential mean to diagnose FD. The authors documented an early plateau during infancy which precedes the symptomatic phase. This can help to identifying a metabolic threshold may lead to new preventive and therapeutic approaches.
First specific therapy for Fabry’s disease is enzyme replacement with recombinant human galactosidase A that provides an exogenous source of deficient enzyme in patients with this progressive disorder. Two drugs are now commercially available: agalsidase alpha and agalsidase beta. A global shortage of agalsidase-β between 2009 and 2012 caused many patients worldwide to be switched from agalsidase-β to agalsidase-α. Skrunes and colleagues [
143] described the effects of switch from agalsidase-β 1.0 mg/kg/every other week (eow) to agalsidase-α 0.2 mg/kg/eow in serial kidney biopsies in 3 patients. Each patient was reassessed by renal biopsy after 5 years of agalsidase-β and 3 years of agalsidase-α. Biopsies after 5 years of agalsidase-β 1.0 mg/kg/eow showed marked clearing of globotriaosylceramide (GL3) from mesangial and endothelial cells and partly cleared podocytes in all patients. After 3 years of agalsidase-α on a lower dose (0.2 mg/kg/eow) there was a reaccumulation of GL3 in podocytes, but not in the mesangium or endothelium. When agalsidase-β was again globally available, one of the patients was reswitched to agalsidase-β with a consequent decrease of podocyte GL3 deposits. These results point out the importance of dose in enzyme replacement therapy (ERT) in preventing irreversible kidney damage.
Congenital myopathies (CM) are a heterogeneous group of muscular disorders characterized by the presence of specific morphologic features on skeletal muscle biopsy. More than 25 genetic causes of CM and several types of mutations within the same gene have been found. Cassandrini et al. [
144] focused on clinical and genetic forms of CM in order to facilitate histological and imaging diagnosis. Based on the results of muscle biopsy can be recognized five forms of CMs: nemaline myopathy (NM), core myopathy, centronuclear myopathy, congenital fiber-type disproportion myopathy, myosin storage myopathy. The morphological hallmark of NM is the presence of nemaline bodies or rods. It is usually considered the most usual form of congenital myopathy, although central core disease can have higher prevalence due to longer term survival. Rod bodies may be present in most muscle fibers, and may occupy over half of a fiber’s volume. In a rare subtype of NM nemaline bodies are present inside myonuclei. There are currently ten known genetic causes of NM, of which the nebulin (NEB) gene, inherited in an autosomal recessive manner, and actin (ACTA1) gene inherited in an autosomal dominant (90%) or recessive (10%) way, are the most important. Core myopathy is an autosomally inherited muscle disorder characterized by the presence of cores in muscle fibers, they can be single or multiple in the same muscle fiber. The disease is associated with defects in the RYR1 gene located on the chromosomal region 19q12–13.2. There are some families in which no abnormality has been found in the RYR1 gene, thus suggesting that mutations in other unidentified genes may be responsible in a minority of families. The other forms of CM are relatively rare. Identification of the true gene mutation is indispensable for a better clinical stratification. However, it is difficult establishing a correct genetic diagnosis for CM. New clinical and histological phenotypes are still being identified for some of the known disease genes and this for many reasons. Furthermore, mutations in different genes can cause many of the histological patterns, and mutations in a single gene can result in various histopathological abnormalities. New genetic approaches are being devised, such as full genome sequencing, which are likely to overcome this barrier and allow even the rarest genetic disorders to be genetically characterized.
As seen, the most important diagnostic clues of congenital myopathies are the presence of particular abnormalities of muscle fiber architecture on muscle biopsy. Witting et al. [
145] reported a comprehensive analysis of the prevalence, genotype, and phenotype of CM in patients 5 years and older in Denmark. After identifying all registered Danish patients with a diagnosis of CM aged older than 5 years, comprehensive clinical, histopathologic, and genetic investigations were performed. Of 82 patients included in the study, 41 had specific histology. A core myopathy was detected in 14 (17%), a centronuclear myopathy (CNM) in 15 (18%), and nemaline myopathy (NM) in 12 (15%). The other patients had undistinctive features on biopsy. A genetic etiology was reached for 83% of patients with histopathologic features of core myopathy CNM, or NM but only for 29% of patients with unspecific histopathologic features (56% of overall cases). The authors also found that the prevalence of CM in Danish patients older than 5 years was 2:100,000 significantly lower than previous studies. This may be due to the exclusion of pediatric patients who have succumbed to their illness prior to age 5. This approach allowed for a unique prospective assessment of this patient group that has not been studied previously in CM.
Congenital NM due to mutations in troponin T1 (TNNT1) has hitherto only been described as a result of a single homozygous nonsense founder mutation in patients of Amish origin and in other individuals with 4 different recessive mutations. Konersman and colleagues [
146] described a novel heterozygous missense mutation of TNNT1 responsible of NM. Blood samples from members of an extended family with Ashkenazi Jewish ancestry underwent Sanger sequencing for TNNT1. The history of the family revealed multiple cases of myopathy in three different generations and a mild phenotype with considerable clinical heterogeneity. Skeletal muscle biopsies showed severe type 1 fiber hypotrophy, with many red/purple-staining rod-like structures exclusively in type 1 fibers. Genetic testing showed the presence of a novel heterozygous missense variants in exon 9 of the gene TNNT1 c.311A > T. This mutation was transmitted in an autosomal dominant fashion whilst, all of the previously described mutations were autosomal recessive cases of TNNT1-related NEM. This report expands the phenotype associated with TNNT1 mutations and may lead clinicians to suspect NEM5 outside the Amish population particularly in mild cases of NM with nemaline rods and an autosomal dominant pattern of inheritance.