Huntington disease is a neurodegenerative disorder that involves preferential atrophy in the striatal complex and related subcortical nuclei. In this paper, which is based on a dataset extracted from the PREDICT-HD study, we use statistical shape analysis with deformation markers obtained through Large Deformation Diffeomorphic Metric Mapping of cortical surfaces to highlight specific atrophy patterns in the caudate, putamen, and globus pallidus, at different prodromal stages of the disease. Based on the relation to cortico-basal-ganglia circuitry, we propose that statistical shape analysis, along with other structural and functional imaging studies, may help expand our understanding of the brain circuitry affected and other aspects of the neurobiology of HD, and also guide the most effective strategies for intervention.

The focus in predictive testing for Huntington disease is beginning to shift from individuals at risk to an examination of the effects on other relatives, particularly on spouses and partners. We examine the effects of participating in a predictive testing program for 25 couples. When assessed prior to testing, spouses were significantly more depressed than their at-risk partners. After pretest counseling, 6 (24%) of the couples chose not to pursue testing. At baseline, these 6 couples had significantly higher levels of psychological distress and marital dysfunction than couples who did choose to complete testing. Of the 19 couples completing testing, 5 received an increased risk result and 14 received a decreased risk result. Prior to testing, the partners of individuals who later received an increased risk result exhibited higher levels of marital distress. At 3- and 6-month follow-ups, high-risk couples were significantly more distressed than low-risk couples. These levels of distress improved somewhat at 9 months after testing, but began to climb again at 12 months. Individuals at increased risk were significantly more distressed at all points during follow-up as compared to individuals at low risk. No significant differences were found between the partners of high- and low-risk individuals at 3, 6, 9, and 12 months after disclosure.(ABSTRACT TRUNCATED AT 250 WORDS)

The Huntington Study Group PHAROS Investigators IMPORTANCE Identifying measures that are associated with the cytosine-adenine-guanine (CAG) expansion in individuals before diagnosis of Huntington disease (HD) has implications for designing clinical trials. OBJECTIVE To identify the earliest features associated with the motor diagnosis of HD in the Prospective Huntington at Risk Observational Study (PHAROS). DESIGN, SETTING, AND PARTICIPANTS A prospective, multicenter, longitudinal cohort study was conducted at 43 US and Canadian Huntington Study Group research sites from July 9, 1999, through December 17, 2009. Participants included 983 unaffected adults at risk for HD who had chosen to remain unaware of their mutation status. Baseline comparability between CAG expansion (Ն37 repeats) and nonexpansion (<37 repeats) groups was assessed. All participants and investigators were blinded to individual CAG analysis. A repeated-measures analysis adjusting for age and sex was used to assess the divergence of the linear trend between the expanded and nonexpanded groups. Data were analyzed from April 27, 2010, to September 3, 2013. EXPOSURE Huntington disease mutation status in individuals with CAG expansion vs without CAG expansion. MAIN OUTCOMES AND MEASURES Unified Huntington's Disease Rating Scale motor (score range, 0-124; higher scores indicate greater impairment), cognitive (symbol digits modality is the total number of correct responses in 90 seconds; lower scores indicate greater impairment), behavioral (score range, 0-176; higher scores indicate greater behavioral symptoms), and functional (Total Functional Capacity score range, 0-13; lower scores indicate reduced functional ability) domains were assessed at baseline and every 9 months up to a maximum of 10 years. RESULTS Among the 983 research participants at risk for HD in the longitudinal cohort, 345 (35.1%) carried the CAG expansion and 638 (64.9%) did not. The mean (SD) duration of follow-up was 5.8 (3.0) years. At baseline, participants with expansions had more impaired motor (3.0 [4.2] vs 1.9 [2.8]; P < .001), cognitive (P < .05 for all measures except Verbal Fluency, P = .52), and behavioral domain scores (9.4 [11.4] vs 6.5 [8.5]; P < .001) but not significantly different measures of functional capacity (12.9 [0.3] vs 13.0 [0.2]; P = .23). With findings reported as mean slope (95% CI), in the longitudinal analyses, participants with CAG expansions showed significant worsening in motor (0.84 [0.73 to 0.95] vs 0.03 [−0.05 to 0.11]), cognitive (−0.54 [−0.67 to −0.40] vs 0.22 [0.12 to 0.32]), and functional (−0.08 [−0.09 to −0.06] vs −0.01 [−0.02 to 0]) measures compared with those without expansion (P < .001 for all); behavioral domain scores did not diverge significantly between groups. CONCLUSIONS AND RELEVANCE Using these prospectively accrued clinical data, relatively large treatment effects would be required to mount a randomized, placebo-controlled clinical trial involving premanifest HD individuals who carry the CAG expansion.

Kousseff syndrome was originally described by Boris Kousseff in 1984: Pediatrics 74:395-398 in three siblings whose main features were conotruncal heart defects, neural tube defects, and dysmorphic features. The proband is a white male who has spina bifida, shunted hydrocephalus, cleft palate, short stature, cognitive impairment, and the typical craniofacial features of velo-cardio-facial syndrome (VCFS), including low-set and dysplastic ears, broad base of the nose, narrow alae nasi, and retrognathia. The family history is significant for a brother who died at 2 weeks of age with myelomeningocele, hydrocephalus, transposition of the great vessels, and unilateral renal agenesis, and a sister who died at 11 days of age with myelomeningocele, truncus arteriosus, hypocalcemia, and autopsy findings of absent thymus and parathyroid glands, consistent with DiGeorge anomaly. Given the clinical findings, family history, and recent knowledge that open neural tube defects can occur in VCFS/DiGeorge anomaly, FISH analysis for 22q11-13 deletion was performed on the proband. A deletion was detected in him and subsequently confirmed in his father. Molecular analysis on autopsy material confirmed the deletion in the proband's deceased brother. We suggest that individuals with neural tube defects associated with other anomalies such as congenital heart defects or cleft palate be evaluated for 22q deletions.

Background: Infants with a positive cystic fibrosis (CF) newborn screen, only one identified CFTR mutation (NBS+/1 mut), and an initial intermediate sweat chloride (30-59 mmol/L) should have repeat sweat chloride testing (SCT). However, the outcome of repeat SCT and the relationship between initial sweat Cl and subsequent CF diagnosis have not been reported.Objective: The objective of this study was to analyze the outcomes of repeat SCT and subsequent CF diagnosis in NBS+/1 mut infants based on their initial sweat chloride concentration. Methods:We retrospectively identified all infants born in Indiana from 2007 to 2017 with NBS+/1 mut and initial SCT in the intermediate range. For each infant, we recorded the initial and repeat SCT results and/or a final CF diagnosis.Results: From 2007 through 2017 there were 2822 NBS+/1 mut infants of which 2613 (82%) had at least one SCT result. No infants with an initial SCT of 30-39 mmol/L were subsequently diagnosed with CF. Of the 31 infants with an initial SCT of 40-49 mmol/L, only 1 was subsequently diagnosed with CF. In contrast, 61% of those with SCTs of 50-59 mmol/L were later diagnosed with CF. Conclusion:These results suggest that infants with a positive NBS for CF and one CFTR mutationwhose initial sweat chloride concentration is 50-59 mmol/L need to be monitored more closely forCF with strong consideration for earlier repeat SCTs and immediate genotypingCystic fibrosis (CF) is an autosomal recessive genetic disease caused by mutations in the gene coding for the CF transmembrane conductance regulator (CFTR). 1 Early diagnosis of CF through newborn screen (NBS) is associated with improved nutritional outcomes and survival, and since 2010, CF NBS has been universally offered in the USA. [2][3][4][5] Although CF NBS algorithms vary from state to state, most utilize a combination of immunoreactive trypsinogen (IRT) measurement followed by CFTR mutation analysis if the IRT exceeds a certain threshold (IRT/DNA method). Infants with an elevated IRT and one CFTR mutation (NBS+/1 mut) should have sweat chloride testing (SCT). 6