Summary Background Fetal alcohol spectrum disorder (FASD) is related to many comorbidities because of the permanent effects of prenatal alcohol exposure on the fetus. We aimed to identify the ...comorbid conditions that co-occur in individuals with FASD and estimate the pooled prevalence of comorbid conditions occurring in individuals with fetal alcohol syndrome (FAS). Methods We did a systematic literature search of studies reporting on the comorbidity and cause of death in individuals with FASD using multiple electronic bibliographic databases, searching for studies published up to July, 2012. We included original research published in a peer-reviewed journal in the English language. We used the following criteria for determining study quality: use of an established FASD diagnostic guideline, study setting, method of data collection, and sample size. All comorbid disease conditions were coded according to the International Classification of Diseases, tenth revision (ICD-10). To estimate the pooled prevalence of comorbid conditions found to co-occur in individuals with FAS, we did meta-analyses assuming a random-effects model. Findings Of 5068 studies found, 127 met eligibility criteria for data extraction. From those studies, we identified 428 comorbid conditions co-occurring in individuals with FASD, spanning across 18 of 22 chapters of the ICD-10. The most prevalent disease conditions were within the sections of congenital malformations, deformities, and chromosomal abnormalities, and mental and behavioural disorders. 33 studies reported data for frequency in a total of 1728 participants with FAS. The five comorbid conditions with the highest pooled prevalence (between 50% and 91%) included abnormal results of function studies of peripheral nervous system and special senses, conduct disorder, receptive language disorder, chronic serous otitis media, and expressive language disorder. Interpretation The high prevalence of comorbid conditions in individuals with FASD highlights the importance of assessing prenatal alcohol exposure as a substantial clinical risk factor for comorbidity. The harmful effects of alcohol on a developing fetus represent many cases of preventable disability, and thus, alcohol use during pregnancy should be recognised as a public health problem globally. Funding Public Health Agency of Canada.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Kabuki syndrome (KS) is a clinically recognisable syndrome in which 70% of patients have a pathogenic variant in
or
. Understanding the function of these genes opens the door to targeted therapies. ...The purpose of this report is to propose diagnostic criteria for KS, particularly when molecular genetic testing is equivocal.
An international group of experts created consensus diagnostic criteria for KS. Systematic PubMed searches returned 70 peer-reviewed publications in which at least one individual with molecularly confirmed KS was reported. The clinical features of individuals with known mutations were reviewed.
The authors propose that a definitive diagnosis can be made in an individual of any age with a history of infantile hypotonia, developmental delay and/or intellectual disability, and one or both of the following major criteria: (1) a pathogenic or likely pathogenic variant in
or
; and (2) typical dysmorphic features (defined below) at some point of life. Typical dysmorphic features include long palpebral fissures with eversion of the lateral third of the lower eyelid and two or more of the following: (1) arched and broad eyebrows with the lateral third displaying notching or sparseness; (2) short columella with depressed nasal tip; (3) large, prominent or cupped ears; and (4) persistent fingertip pads. Further criteria for a probable and possible diagnosis, including a table of suggestive clinical features, are presented.
As targeted therapies for KS are being developed, it is important to be able to make the correct diagnosis, either with or without molecular genetic confirmation.
Fetal alcohol spectrum disorder (FASD) is one of the most disabling potential outcomes of prenatal alcohol exposure. The population-based prevalence of FASD among the general population of Canada was ...unknown. The objective of this study was to determine the population-based prevalence of FASD among elementary school students, aged 7 to 9 years, in the Greater Toronto Area (GTA) in Ontario, Canada.
This screening study used a cross-sectional, observational design utilizing active case ascertainment, along with retrospective collection of prenatal alcohol exposure information. Data collection involved two phases. Phase I consisted of taking growth measurements, a dysmorphology examination, and obtaining a history of behavioral and/or learning problems. Phase II consisted of a neurodevelopmental assessment, maternal interview, and behavioral observations/ratings by parents/guardians. Final diagnostic screening conclusions were made by consensus by a team of experienced multidisciplinary experts during case conferences, using the 2005 Canadian guidelines for FASD diagnosis. The prevalence of FASD was estimated, taking into consideration the selection rate, which was used to account for students who dropped out or were lost to follow-up during each phase. Monte Carlo simulations were employed to derive the confidence interval (CI) for the point estimates.
A total of 2555 students participated. A total of 21 cases of suspected FASD were identified. The prevalence of FASD was estimated to be 18.1 per 1000, or about 1.8%. Using a less conservative approach (sensitivity analysis), the prevalence of FASD was estimated to be 29.3 per 1000, or about 2.9%. Therefore, the population-based prevalence of FASD is likely to range between 2 and 3% among elementary school students in the GTA in Ontario, Canada.
This study provides the first population-based estimate of the prevalence of FASD in Canada. The estimate is approximately double or possibly even triple previous crude estimates. FASD prevalence exceeds that of other common birth defects such as Down's syndrome, spina bifida, trisomy 18, as well as autism spectrum disorder in Canada. More effective prevention strategies targeting alcohol use during pregnancy, surveillance of FASD, and timely interventions and support to individuals with FASD and their families are urgently needed.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. ...Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
CODAS syndrome is a multi-system developmental disorder characterized by cerebral, ocular, dental, auricular, and skeletal anomalies. Using whole-exome and Sanger sequencing, we identified four LONP1 ...mutations inherited as homozygous or compound-heterozygous combinations among ten individuals with CODAS syndrome. The individuals come from three different ancestral backgrounds (Amish-Swiss from United States, n = 8; Mennonite-German from Canada, n = 1; mixed European from Canada, n = 1). LONP1 encodes Lon protease, a homohexameric enzyme that mediates protein quality control, respiratory-complex assembly, gene expression, and stress responses in mitochondria. All four pathogenic amino acid substitutions cluster within the AAA+ domain at residues near the ATP-binding pocket. In biochemical assays, pathogenic Lon proteins show substrate-specific defects in ATP-dependent proteolysis. When expressed recombinantly in cells, all altered Lon proteins localize to mitochondria. The Old Order Amish Lon variant (LONP1 c.2161C>Gp.Arg721Gly) homo-oligomerizes poorly in vitro. Lymphoblastoid cell lines generated from affected children have (1) swollen mitochondria with electron-dense inclusions and abnormal inner-membrane morphology; (2) aggregated MT-CO2, the mtDNA-encoded subunit II of cytochrome c oxidase; and (3) reduced spare respiratory capacity, leading to impaired mitochondrial proteostasis and function. CODAS syndrome is a distinct, autosomal-recessive, developmental disorder associated with dysfunction of the mitochondrial Lon protease.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Head circumference is used together with other measures as a proxy for central nervous system damage in the diagnosis of fetal alcohol spectrum disorders, yet the relationship between head ...circumference and brain volume has not been investigated in this population. The objective of this study is to characterize the relationship between head circumference, brain volume and cognitive performance in a large sample of children with prenatal alcohol exposure (n = 144) and healthy controls (n = 145), aged 5-19 years. All participants underwent magnetic resonance imaging to yield brain volumes and head circumference, normalized to control for age and sex. Mean head circumference, brain volume, and cognitive scores were significantly reduced in the prenatal alcohol exposure group relative to controls, albeit with considerable overlap between groups. Males with prenatal alcohol exposure had reductions in all three measures, whereas females with prenatal alcohol exposure had reduced brain volumes and cognitive scores, but no difference in head circumference relative to controls. Microcephaly (defined here as head circumference ≤ 3rd percentile) occurred more often in prenatal alcohol exposed participants than controls, but 90% of the exposed sample had head circumferences above this clinical cutoff indicating that head circumference is not a sensitive marker of prenatal alcohol exposure. Normalized head circumference and brain volume were positively correlated in both groups, and subjects with very low head circumference typically had below-average brain volumes. Conversely, over half of the subjects with very low brain volumes had normal head circumferences, which may stem from differential effects of alcohol on the skeletal and nervous systems. There were no significant correlations between head circumference and any cognitive score. These findings confirm group-level reductions in head circumference and increased rates of microcephaly in children with prenatal alcohol exposure, but raise concerns about the predictive value of this metric at an individual-subject level.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Fetal Alcohol Spectrum Disorder (FASD) is underdiagnosed in Canada. The diagnosis of FASD is not simple and currently, the recommendation is that a comprehensive, multidisciplinary assessment of the ...individual be done. The purpose of this study was to estimate the annual cost of FASD diagnosis on Canadian society.
The diagnostic process breakdown was based on recommendations from the Fetal Alcohol Spectrum Disorder Canadian Guidelines for Diagnosis. The per person cost of diagnosis was calculated based on the number of hours (estimated based on expert opinion) required by each specialist involved in the diagnostic process. The average rate per hour for each respective specialist was estimated based on hourly costs across Canada. Based on the existing clinical capacity of all FASD multidisciplinary clinics in Canada, obtained from the 2005 and 2011 surveys conducted by the Canada Northwest FASD Research Network, the number of FASD cases diagnosed per year in Canada was estimated. The per person cost of FASD diagnosis was then applied to the number of cases diagnosed per year in Canada in order to calculated the overall annual cost.
Using the most conservative approach, it was estimated that an FASD evaluation requires 32 to 47 hours for one individual to be screened, referred, admitted, and diagnosed with an FASD diagnosis, which results in a total cost of $3,110 to $4,570 per person. The total cost of FASD diagnostic services in Canada ranges from $3.6 to $5.2 million (lower estimate), up to $5.0 to $7.3 million (upper estimate) per year.
As a result of using the most conservative approach, the cost of FASD diagnostic services presented in the current study is most likely underestimated. The reasons for this likelihood and the limitations of the study are discussed.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Autosomal-recessive inheritance, severe to profound sensorineural hearing loss, and partial agenesis of the corpus callosum are hallmarks of the clinically well-established Chudley-McCullough ...syndrome (CMS). Although not always reported in the literature, frontal polymicrogyria and gray matter heterotopia are uniformly present, whereas cerebellar dysplasia, ventriculomegaly, and arachnoid cysts are nearly invariant. Despite these striking brain malformations, individuals with CMS generally do not present with significant neurodevelopmental abnormalities, except for hearing loss. Homozygosity mapping and whole-exome sequencing of DNA from affected individuals in eight families (including the family in the first report of CMS) revealed four molecular variations (two single-base deletions, a nonsense mutation, and a canonical splice-site mutation) in the G protein-signaling modulator 2 gene, GPSM2, that underlie CMS. Mutations in GPSM2 have been previously identified in people with profound congenital nonsyndromic hearing loss (NSHL). Subsequent brain imaging of these individuals revealed frontal polymicrogyria, abnormal corpus callosum, and gray matter heterotopia, consistent with a CMS diagnosis, but no ventriculomegaly. The gene product, GPSM2, is required for orienting the mitotic spindle during cell division in multiple tissues, suggesting that the sensorineural hearing loss and characteristic brain malformations of CMS are due to defects in asymmetric cell divisions during development.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Floating-Harbor syndrome (FHS) is a rare condition characterized by short stature, delayed osseous maturation, expressive-language deficits, and a distinctive facial appearance. Occurrence is ...generally sporadic, although parent-to-child transmission has been reported on occasion. Employing whole-exome sequencing, we identified heterozygous truncating mutations in SRCAP in five unrelated individuals with sporadic FHS. Sanger sequencing identified mutations in SRCAP in eight more affected persons. Mutations were de novo in all six instances in which parental DNA was available. SRCAP is an SNF2-related chromatin-remodeling factor that serves as a coactivator for CREB-binding protein (CREBBP, better known as CBP, the major cause of Rubinstein-Taybi syndrome RTS). Five SRCAP mutations, two of which are recurrent, were identified; all are tightly clustered within a small (111 codon) region of the final exon. These mutations are predicted to abolish three C-terminal AT-hook DNA-binding motifs while leaving the CBP-binding and ATPase domains intact. Our findings show that SRCAP mutations are the major cause of FHS and offer an explanation for the clinical overlap between FHS and RTS.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The information on the nutrition status of women at-risk of carrying a child with fetal alcohol spectrum disorder (FASD) is scarce, particularly in the First Nations population living on reserve. ...This study examined and compared nutrition status, dietary intake, and lifestyle patterns of pregnant at-risk, defined as those who consume alcoholic drink during the current pregnancy, and non-at-risk women living in northern Manitoban community. Thirty-seven pregnant, First Nations women (at-risk n = 15; non-at-risk, n = 22) were recruited to participate in the study. A questionnaire, presented in paper and iPad formats, collected information on participants’ demographics, dietary intake, lifestyle, pregnancy outcomes, and maternal health. A food frequency questionnaire and 24-h recall were used to determine nutrient intake. Nutrient values were assessed using Dietary Reference Intakes (DRI). At-risk and non-at-risk women were below the Canada Food Guide serving size recommended for Vegetable and Fruit, Grain, and Milk Products with 93%, 92%, and 93% of participants not meeting the recommendations, respectively. Women met the recommendations for vitamins A, B1, B12, C, niacin, choline, as well as calcium, and zinc. Sixty eight percentage (%) of participants did not meet the recommendations for folate and iron, and 97% for docosahexaenoic acid (DHA). Significant differences were observed between non-at-risk and at-risk women for mean % DRI intakes of vitamin C (313 ± 224 vs. 172 ± 81 mg/day), niacin (281 ± 123 vs. 198 ± 80 mg/day), folate (70 ± 38 vs. 10 ± 22 mcg/day), and iron (101 ± 74 vs. 74 ± 30 mg/day). The findings of this study lay a fundamental premise for the development of community nutrition programs, nutrition education, and nutrition intervention, such as community specific prenatal supplementation. These will assist in ensuring adequate maternal nutrient intake and benefit families and communities in Northern Manitoba with and without alcohol insult.
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