Laura Weissman

Clinical genetic testing for patients with autism spectrum disorders

BACKGROUND: Multiple lines of evidence indicate a strong genetic contribution to autism spectrum disorders (ASDs). Current guidelines for clinical genetic testing recommend a G-banded karyotype to detect chromosomal abnormalities and fragile X DNA testing, but guidelines for chromosomal microarray analysis have not been established. PATIENTS AND METHODS: A cohort of 933 patients received clinical genetic testing for a diagnosis of ASD between January 2006 and December 2008. Clinical genetic testing included G-banded karyotype, fragile X testing, and chromosomal microarray (CMA) to test for submicroscopic genomic deletions and duplications. Diagnostic yield of clinically significant genetic changes was compared. RESULTS: Karyotype yielded abnormal results in 19 of 852 patients (2.23% [95% confidence interval (CI): 1.73%–2.73%]), fragile X testing was abnormal in 4 of 861 (0.46% [95% CI: 0.36%–0.56%]), and CMA identified deletions or duplications in 154 of 848 patients (18.2% [95% CI: 14.76%–21.64%]). CMA results for 59 of 848 patients (7.0% [95% CI: 5.5%–8.5%]) were considered abnormal, which includes variants associated with known genomic disorders or variants of possible significance. CMA results were normal in 10 of 852 patients (1.2%) with abnormal karyotype due to balanced rearrangements or unidentified marker chromosome. CMA with whole-genome coverage and CMA with targeted genomic regions detected clinically relevant copy-number changes in 7.3% (51 of 697) and 5.3% (8 of 151) of patients, respectively, both higher than karyotype. With the exception of recurrent deletion and duplication of chromosome 16p11.2 and 15q13.2q13.3, most copy-number changes were unique or identified in only a small subset of patients. CONCLUSIONS: CMA had the highest detection rate among clinically available genetic tests for patients with ASD. Interpretation of microarray data is complicated by the presence of both novel and recurrent copy-number variants of unknown significance. Despite these limitations, CMA should be considered as part of the initial diagnostic evaluation of patients with ASD.

Copy number variation plays an important role in clinical epilepsy

To evaluate the role of copy number abnormalities detectable using chromosomal microarray (CMA) testing in patients with epilepsy at a tertiary care center.

A phase I study of high-dose ifosfamide and escalating doses of carboplatin with autologous bone marrow support.

The dose-limiting toxicity in two separate phase I trials of the high-dose single agents ifosfamide and carboplatin was renal insufficiency at 18 g/m2 and hepatic and ototoxicity at 2,400 mg/m2, respectively. In this phase I study, 16 adults were treated with ifosfamide at 75% of the single-agent maximum-tolerated dose (MTD) (12 g/m2) and escalating doses of carboplatin (400 to 1,600 mg/m2) to determine the nonhematologic dose-limiting toxicity and the maximum-tolerated dose of the combination. Both drugs as well as mesna for uroprotection were given by continuous infusion over 4 days with an additional day of mesna (total dose per course, 15 g/m2). Autologous bone marrow support was stipulated for subsequent dose levels once granulocytes remained less than 500/microL for more than 14 days in two of three to five patients entered at a given dose level. Autologous bone marrow support was used at doses above the 400 mg/m2 carboplatin dose level. At the maximum-tolerated dose level of 1,600 mg/m2 of carboplatin, renal toxicity precluded further dose escalation. Of the five patients entered at this dose level, reversible creatinine elevation greater than 2 mg/dL (median peak, 2.6 mg/dL) was observed in three patients, and irreversible renal failure occurred in an additional patient (peak creatinine, 6.9 mg/dL. Transient gross hematuria appeared more common with the combination than with ifosfamide alone. Two patients developed severe somnolence and confusion associated with a rising creatinine. There were two complete (CRs) and four partial responses (PRs) in 14 heavily pretreated assessable patients (including four partial or complete responses in eight assessable patients with advanced refractory sarcoma, and one CR in two patients with germ cell carcinoma). Carboplatin and ifosfamide appear to have overlapping renal toxicity. Nevertheless, carboplatin and ifosfamide can be combined at 80% and 75% of the single-agent maximum-tolerated doses, respectively, with acceptable nonhematologic toxicity. Ifosfamide and carboplatin are an attractive core combination for further studies in the treatment of sarcoma, germ cell, ovarian, and lung carcinomas.

SOX12 and NRSN2 are candidate genes for 20p13 subtelomeric deletions associated with developmental delay

20p13 telomeric/subtelomeric deletions are clinically significant but are currently under‐investigated. So far only five molecularly delineated cases have been reported in literature and no candidate genes have been sufficiently implicated. Here, we present six new deletion cases identified by chromosomal microarray analysis (CMA). We also review 32 cases combined from literature and databases. We found that most 20p13 deletion patients exhibit significant developmental delay. Dysmorphic features are common but a consistent pattern was not recognized. Reduced cognitive ability was frequent. Based on pathogenic deletions delineated in this study, we mapped the smallest overlapping region and identified two nervous system expressing genes (SOX12 and NRSN2) as candidate genes that may be involved in the developmental defects in 20p13 microdeletion.

Escalating doses of carboplatin with high-dose ifosfamide using autologous bone marrow as support: a phase I study.

SummaryIn this phase I study, 16 adult cancer patients were treated with concurrent 4-day continuous infusions of ifosfamide at 12 g/m2 and escalating doses of carboplatin (400–1600 mg/m2) to determine the major non-haematological dose-limiting toxicity of the combination. Mesna was given by continuous infusion over 5 days for uroprotection (total dose per course=15 g/m2). Autologous bone marrow support, which was mandated for subsequent dose levels once granulocytes remained below 500/μl for more than 14 days in at least 2 patients entered at a given dose level, was used at dose levels above 400 mg/m2 carboplatin. Renal toxicity became doselimiting at the maximum tolerated dose level of 1600 mg/ m2 carboplatin. Temporary creatinine elevations above 2 mg/dl (median peak 2.6 mg/dl) were observed in 3 and irreversible renal toxicity occurred in 1 (peak creatinine 6.9 mg/dl, chronic creatinine 5–6 mg/dl) of the 5 patients entered at this dose level. Severe confusion and lethargy associated with rising creatinine developed in 2 patients. Two complete and four partial responses were documented in 14 heavily pretreated evaluable patients. The complete responses continue at 14+ and 20+ months in a patient with germ cell carcinoma and Ewings sarcoma, respectively. Carboplatin appears to contribute to the renal toxicity of ifosfamide. Nevertheless, the combination of carboplatin and ifosfamide at 80% and 75% of the single-agent maximal tolerated doses respectively produced acceptable non-haematological toxicity. Further studies in the treatment of sarcoma, germ cell, ovarian and lung carcinomas with this combination are warranted.

Autism After DSM 5: The Potential Impact in One Childʼs Case

CASE Max is a 21-month old boy with speech and language delay presenting for diagnostic clarification and treatment recommendations. Max was born at 37 weeks after a twin gestation. He is medically healthy and lives at home with supportive parents and a typically developing twin sister. Max began speech and language therapy when he was 14 months old.Max spoke his first word at 16 months. He uses fewer than 10 words or word approximations; however, he does not use these words spontaneously to communicate. Max has decreased use of eye contact and rarely uses nonverbal means of communication. Max whines but does not point or reference his parents to request their help when he wants something out of reach. Max responds to 1-step directions about 50% of the time. An audiology assessment was normal. Max does not bring objects of interest to show others, rarely initiates interactions and does not consistently respond to social overtures.Max is described as an easy-going child. He is content to play on his own and shows little interest in other children. He likes to spin wheels for the purpose of watching them. Max has no rigidities or rituals and is easy to redirect. He has no sensory seeking behaviors or aversions. He does not engage in any repetitive motor mannerisms.On formal evaluation, Maxs cognitive skills were assessed within the average range; language and gross motor skills were below average. Performance on the Autism Diagnostic Observation Schedule, Toddler Module was concerning for an Autism Spectrum Disorder (ASD).Maxs evaluation was concerning for deficits in social and communication functioning. A new Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) was recently published, resulting in a change in the diagnostic criteria for ASDs. Max meets criteria for autistic disorder under DSM, 4th edition, text revision (DSM-4-TR), but does not meet criteria for an ASD under DSM-5. Specifically by DSM-4-TR, he met all criteria under social interaction, 2 criteria under communication, and 1 under restricted and repetitive behaviors. By DSM-5, he met all of criteria A and just 1 of criteria B. How would you proceed diagnostically and what treatment recommendations would you make?

Progressive ventricular dilatation (PVD) over the past 22 years.

We read with interest the article of Murphy et al ,1 and it prompted us to review our own experience with progressive ventricular dilatation (PVD) over the past 22 years at the Maine Medical Center (MMC). Since 1980, we have used a single approach to management of PVD. As noted in previous publications, we have considered the need for intervention to be rapid head growth defined as an …

Documentation of second-by-second breastfeeding behaviors using a novel method.

The specific way nursing patterns influence the duration of postpartum amenorrhea is unknown. This may result from the shortcomings of available methods: the daily log and recall. We tested these against a novel method, an event monitor (EM), consisting of a wrist-worn stopwatch that stores events. Exclusively breastfeeding women (n=1 1) were assigned randomly to use each of the three methods twice during a 2-week period surrounding Weeks 4, 8, and 12 postpartum. More nursing episodes were recorded with the EM than log during Week 4 (p<0.03) and Week 8 (p<0.02). EM captured more episodes than recall during all study periods (p<0.004). The EM was considered as acceptable and accurate to mothers as the other methods and, therefore, is a useful option for documenting breastfeeding patterns.