Recurrent reciprocal 16p11.2 rearrangements associated with global developmental delay, behavioural problems, dysmorphism, epilepsy, and abnormal head size.

BACKGROUND: Deletion and the reciprocal duplication in 16p11.2 were recently associated with autism and developmental delay. METHOD: We indentified 27 deletions and 18 duplications of 16p11.2 were identified in 0.6% of all samples submitted for clinical array-CGH (comparative genomic hybridisation) analysis. Detailed molecular and phenotypic characterisations were performed on 17 deletion subjects and ten subjects with the duplication. RESULTS: The most common clinical manifestations in 17 deletion and 10 duplication subjects were speech/language delay and cognitive impairment. Other phenotypes in the deletion patients included motor delay (50%), seizures ( approximately 40%), behavioural problems ( approximately 40%), congenital anomalies ( approximately 30%), and autism ( approximately 20%). The phenotypes among duplication patients included motor delay (6/10), behavioural problems (especially attention deficit hyperactivity disorder (ADHD)) (6/10), congenital anomalies (5/10), and seizures (3/10). Patients with the 16p11.2 deletion had statistically significant macrocephaly (p<0.0017) and 6 of the 10 patients with the duplication had microcephaly. One subject with the deletion was asymptomatic and another with the duplication had a normal cognitive and behavioural phenotype. Genomic analyses revealed additional complexity to the 16p11.2 region with mechanistic implications. The chromosomal rearrangement was de novo in all but 2 of the 10 deletion cases in which parental studies were available. Additionally, 2 de novo cases were apparently mosaic for the deletion in the analysed blood sample. Three de novo and 2 inherited cases were observed in the 5 of 10 duplication patients where data were available. CONCLUSIONS: Recurrent reciprocal 16p11.2 deletion and duplication are characterised by a spectrum of primarily neurocognitive phenotypes that are subject to incomplete penetrance and variable expressivity. The autism and macrocephaly observed with deletion and ADHD and microcephaly seen in duplication patients support a diametric model of autism spectrum and psychotic spectrum behavioural phenotypes in genomic sister disorders.

Evidence for genetic heterogeneity in D-2-hydroxyglutaric aciduria.

We performed molecular, enzyme, and metabolic studies in 50 patients with D-2-hydroxyglutaric aciduria (D-2-HGA) who accumulated D-2-hydroxyglutarate (D-2-HG) in physiological fluids. Presumed pathogenic mutations were detected in 24 of 50 patients in the D-2-hydroxyglutarate dehydrogenase (D2HGDH) gene, which encodes D-2-hydroxyglutarate dehydrogenase (D-2-HGDH). Enzyme assay of D-2-HGDH confirmed that all patients with mutations had impaired enzyme activity, whereas patients with D-2-HGA whose enzyme activity was normal did not have mutations. Significantly lower D-2-HG concentrations in body fluids were observed in mutation-positive D-2-HGA patients than in mutation-negative patients. These results imply that multiple genetic loci may be associated with hyperexcretion of D-2-HG. Accordingly, we suggest a new classification: D-2-HGA Type I associates with D-2-HGDH deficiency, whereas idiopathic D-2-HGA manifests with normal D-2-HGDH activity and higher D-2-HG levels in body fluids compared with Type I patients. It remains possible that several classifications for idiopathic D-2-HGA patients with diverse genetic loci will be revealed in future studies.

Abnormal folate metabolism as a risk factor for first-trimester spontaneous abortion.

OBJECTIVE: To assess the potential role of folic acid in early pregnancy loss by measuring homocysteine (hcy) levels in healthy, pregnant women who present with a current first-trimester miscarriage. STUDY DESIGN: This was a cross-sectional analysis comprising 13 patients aged 18-31 years old who had a scheduled dilatation and curettage for a first-trimester miscarriage. The controls were 15 patients of similar maternal age presenting for a first-trimester prenatal care visit. Following completion of a 21-item, structured questionnaire, patients were excluded from the study if they had any known risk factors for a first-trimester miscarriage. The remaining patients provided blood samples for measurement of homocysteine and red blood cell folate. Cases and controls were compared using a standard 2-sample t test. In order to detect a clinically relevant 2.3 micromol/L difference in homocysteine levels, 11 cases and 8 controls were needed. RESULTS: The mean hcy level in cases (5.8 umolmol/L) vs. controls (5.7 micromol/L) was not significantly different (p = 0.83), and all individual values fell within the normal range expected in pregnant women. Red blood cell folate levels (cases=586 ng/mL, controls=611 ng/mL) were also not significantly different (p = 0.72), and no cases of folate deficiency were detected. Maternal age (cases=26, controls=25) and gestational age (cases = 8.8 weeks, controls = 8.4 weeks) were similar between the 2 groups. CONCLUSION: In this community-based pilot study, abnormal folate metabolism was not an apparent risk factor for spontaneous first-trimester pregnancy loss.

Mosaic variegated aneuploidy without microcephaly: implications for cytogenetic diagnosis.

Mosaic variegated aneuploidy (MVA) is a rare condition characterized by multiple trisomies, rarely monosomies, and a non-specific phenotype including microcephaly, growth and mental retardation, mild malformations, and an increased risk of malignancy. We describe a patient with MVA in whom trisomy 19 mosaicism was originally suspected. The patient was the product of an uncomplicated term pregnancy and delivery. Significant findings were mental retardation, obesity, mild epicanthal folds, tapering fingers, relatively small hands and feet, alternating exotropia, nasal speech limited to short phrases, and generalized hypotonia. There is no family history for birth defects, mental retardation, or consanguinity. The initial peripheral blood chromosome study showed trisomy 19 in 4 of 31 metaphase cells. Because mosaic trisomy 19 is rare, the study was extended to 100 cells, wherein two cells with trisomy 8 were identified. A second blood karyotype was obtained and found to be 47,XX,+8[3]/47,XX,+19[3]/47,XX, +18[2]/47,XX,+9[1]/46,XX[91]. Skin fibroblast chromosome studies revealed a 46,XX karyotype in 120 cells examined. There was no evidence of premature centromere separation. Mutations in the BUB1B gene that encodes a key mitotic spindle checkpoint protein have been described in MVA; however, no mutations of this gene were identified in our patient. This case illustrates the importance of considering other possibilities when confronted with an extremely rare diagnosis such as mosaic trisomy 19. In addition, it shows the importance of not simply interpreting a low percentage of multiple aneuploidies as cell culture artifact, because an additional work-up to rule out MVA may be warranted since this diagnosis is associated with an increased risk of malignancy.

Improved growth and nutrition status in children with methylmalonic or propionic acidemia fed an elemental medical food.

BACKGROUND: Failure-to-thrive (FTT) has been described in patients with organic acidemias treated with low protein diets. OBJECTIVE: To determine if patients with methylmalonic (MMA) or propionic acidemia (PA) can achieve normal growth and nutrition status. METHODS: A 6-month multicenter outpatient study was conducted with infants and toddlers treated with Propimex-1 Amino Acid-Modified Medical Food With Iron (Ross Products Division, Abbott Laboratories, Columbus, OH). Main outcome measures were anthropometrics, protein status indices, plasma retinol, and alpha-tocopherol. RESULTS: Sixteen patients completed the study. Mean baseline age was 0.54 +/- 0.02 years (range 0.03-3.00 years). By study end, mean National Center for Health Statistics (NCHS) weight centile increased from 26 to 49%; mean crown-heel length centile from 25 to 33%; and mean head circumference centile from 43 to 54%. Mean (+/- SE) protein and energy intakes by <6-month-old, 6<12-month-old, and 1<4-year-old patients were 15.3 +/- 0.9 g and 645 +/- 10 kcal; 18.3 +/- 1.1 g and 741 +/- 92 kcal; and 25.1 +/- 2.46 g and 1062 +/- 100 kcal, respectively. Plasma glycine concentrations were significantly and negatively correlated with energy intake (r=-0.77, p<0.0005). No correlation was found between dietary protein intakes and plasma ammonia concentrations. Protein status indices, retinol and alpha-tocopherol concentrations were within reference ranges at study end. CONCLUSIONS: Propimex-1 improved growth and nutrition status in patients with MMA or PA in just 6 months when fed in sufficient amounts. Providing energy and protein for patients with FTT at intakes recommended for catch-up growth may have resulted in even better growth.