the AJMG SEQUENCE
In this issue
DIETARY SUPPLEMENTS DON'T IMPROVE ANGELMAN SYNDROME SYMPTOMS
Bird et al (p. 2956) report that supplementation with betaine, metafolin, creatine, and vitamin B12 appears safe but is ineffective in decreasing the severity of Angelman syndrome (AS) symptoms.
AS results from deficient ubiquitin protein ligase 3a, expressed by the UBE3A gene that maps to chromosome 15q 11—ql3. The gene is imprinted such that only the maternally inherited gene is expressed. The paternally inherited UBE3A gene is silenced, a process mediated by an antisense transcript.
The researchers gave a regimen of dietary supplements to 90 participants, 65 of whom completed the study, to promote DNA methylation, alter UBE3A gene expression, and ameliorate symptoms. The researchers performed neurospsychological evaluations, biochemical testing, and assessment of DNA methylation at the beginning and at the end of one year of supplementation. The outcome measures were changes in level of developmental function, biochemical parameters, and global DNA methylation.
After comparing data form these children to a control group from a previous randomized double-blind trial using folic acid and betaine, the researchers found no significant changes in developmental performance, biochemical parameters, and site-specific DNA methylation. They noted several adverse events including worsening of seizures, onset or worsening of sleep problems, constipation, and anorexia.
STEM CELL TRANSPLANT SUGGESTED FOR PEARSON SYNDROME
Hematopoietic stem cell transplantation (HSCT) may be useful in managing Pearson marrow-pancreas syndrome (PS), write Tumiono et al (p. 3063).
Figure 1. Bone marrow sample of patient 3:typical vacuolization of a proerythroblast.
PS is a rare, fatal multisystemic disorder mainly involving the body's system for producing blood, pancreas, liver, and kidneys. Symptoms include high-serum lactate/pyruvate levels and abnormal oxidative phosphorylation in lymphocytes. All tissues in patients with PS reveal mitochondrial DNA (mtDNA) anomalies. Death usually occurs in infancy or early childhood due to metabolic disorders or infections.
The authors report on four patients with PS, one of whom was treated with allogeneic HSCT and showed complete resolution of both hematological and nonhematological issues like metabolic acidosis. The patient died of leukemia, which arose after allogeneic HSCT.
The authors point to another reported use of transplant in a patient with PS who experienced resolved acidosis, lactaddemia, and morphological hepatic abnormalities.
HSCT may also prove useful for the treatment of other severe mitochondrial DNA defect syndromes reguiring transplantation in the early stages of disease, preferably before significant organ and tissue damage appears, the authors add.
FINDINGS ON NEW l7q23.2 DELETION PATIENTS SUGGEST REGION FOR HEARING LOSS GENE
Schönewolf-Greulich et al (p.2964) describe two new patients with 17q23.2 deletion and suggest that a hearing loss gene may be located in the region
Previous research suggests that microdeletion of the 17g23.2 region comprises a new syndrome, based on findings in eight cases with a common phenotype. It includes mild to moderate developmental delay, heart defects, microcephaly, postnatal growth retardation, and hand, foot and limb abnormalities. Three of these cases involved sensorineural hearing loss.
The two new cases include patients with microdeletions at 17q23.l-q23.2, sensorineural hearing loss, speech delay, and mild intellectual disability. These deletions were smaller than the common deleted region for the eight previously described 17q23.2 microdeletion cases.
The five patients with sensorineural hearing loss described in both studies all had a microdeletion at17q23.2, suggesting the presence of a candidate gene for hearing loss within this region. Other research has suggested TBX4, the gene responsible for the heart or limb defects observed in 17q23.2 deletion patients, but the present two cases do not have these features, despite deletion of this gene, the researchers write.
Figure 1. Clinical pictures of the two reported cases. Patient 1 at age 7 years (A) and Patient 2 at age 9 years.