Jennifer A. Sullivan

Hepatocellular carcinoma in glycogen storage disease type Ia: a case series.

SummaryWe present a series of 8 patients (6 males, 2 females) with hepatocellular carcinoma (HCC) and glycogen storage disease type Ia (GSD Ia). In this group, the age at which treatment was initiated ranged from birth to 39 years (mean 9.9 years). All patients but one were noncompliant with treatment. Hepatic masses were first detected at an age range of 13–45 years (mean 28.1 years). Age at diagnosis of HCC ranged from 19 to 49 years (mean 36.9 years). Duration between the diagnosis of liver adenomas and the diagnosis of HCC ranged from 0 to 28 years (mean 8.8 years, SD=11.5). Two patients had positive hepatitis serologies (one hepatitis B, one hepatitis C). α-Fetoprotein (AFP) was normal in 6 of the 8 patients. Carcinoembryonic antigen (CEA) was normal in the 5 patients in which it was measured. Current guidelines recommend abdominal ultrasonography with AFP and CEA levels every 3 months once patients develop hepatic lesions. Abdominal CT or MRI is advised when the lesions are large or poorly defined or are growing larger. We question the reliability of AFP and CEA as markers for HCC in GSD Ia. Aggressive interventional management of masses with rapid growth or poorly defined margins may be necessary to prevent the development of HCC in this patient population.

Parental attitudes regarding carrier testing in children at risk for fragile X syndrome

Sixty-five parents of individuals affected by fragile X syndrome who attended the National Fragile X Conference in Portland, Oregon (1996), were asked to complete a survey assessing parental level of concern about carrier testing in children at risk for fragile X syndrome. All subjects completed a 15-item paper and pencil Likert response scale measure that was developed specifically for this study. The items included parental rights and duties, psychological adjustment, adaptation, discrimination, harm, childbearing, and interpersonal relationships. The major concern of the parents was that their children have knowledge of their carrier status prior to becoming sexually active and that their children be able to marry informed of their genetic risk. Mothers were significantly more concerned than fathers about raising their children with the knowledge of their carrier status. A sense of parental right to make the decision regarding carrier testing for children was associated with concerns about (1) behavioral or educational problems, (2) knowledge of carrier status prior to sexual activity or marriage, and (3) adjustment of the children to knowledge of their carrier status. As the sample was drawn from a unique population of parents, the results of this survey should be interpreted with caution. The findings of this study suggest a model of parents providing anticipatory guidance for their children to help them adjust to carrier information and for their children to have this knowledge prior to the possibility of reproduction.

Donepezil for the treatment of language deficits in adults with Down syndrome: a preliminary 24-week open trial.

At present, there is no proven pharmacologic treatment for cognitive or language impairments in Down syndrome (DS). Cholinergic deficits have been documented in DS and linked to cognitive deficits. This study is a 24‐week open‐label clinical trial of donepezil hydrochloride for the treatment of language deficits in adults with DS. To our knowledge, this is the first prospective study to evaluate systematically the effects of donepezil, a cholinesterase inhibitor, on specific language domains in DS. The main finding that emerged was an improvement in expressive language performance following donepezil therapy. Despite the multiple methodological limitations, the results raise important questions regarding the role of the cholinergic system in language function and the specific effect of cholinergic therapy in the treatment of language impairment in DS. The results support the need for large‐scale controlled studies of the effects of donepezil treatment on language and on other cognitive domains in DS.

Donepezil effects on language in children with Down syndrome: Results of the first 22-week pilot clinical trial

To the Editor: In earlier pilot studies, we reported improvements in global function [Kishnani et al., 1999] and expressive language function [Heller et al., 2003] in adults with Down syndrome (DS) following cholinergic therapy (donepezil hydrochloride). In this study, we report results of a small open-label clinical trial of donepezil in children with DS. To our knowledge, this is the first study evaluating the effects of donepezil on language in children with DS. After obtaining IRB approval and written informed consent, we enrolled seven children (2M:5F) between the ages of 8 and 13 years (mean age = 10.5 years) with DS (trisomy 21 by blood chromosome analysis) and their primary caregivers in a prospective open trial of donepezil. All subjects were verbal, able to hear speech at a conversational level, and able to ingest oral medication. None of the subjects had active thyroid disease, vitamin B12 deficiency, clinically-confirmed pregnancy, or clinically-significant systemic disorders, (e.g., bradycardia (HR < 50), insulin-dependent diabetes mellitus, active peptic ulcer, celiac disease, significant reactive airways, or seizure disorder) at the time of entry into the trial. They had not previously ingested cholinesterase inhibitors or any other investigational or alternative therapies used to treat the symptoms of DS in the 30 days prior to or during the trial. IQs of six subjects (obtained from school reports) ranged from 46 to 66 (mean IQ = 50). The IQ of one subject could not be determined from records. This 22-week trial (16 week open treatment study followed by a 6-week washout) was completed at the General Clinical Outpatient Research Unit at Duke University Medical Center. Subjects attended four sessions, week 0 (baseline), week 8 (low dose), week 16 (high dose), and week 22 (washout). At the completion of the baseline visit, donepezil was dosed orally at 2.5 mg once daily for 8 weeks. Based on tolerability, the dose was increased to 5 mg daily for the remaining 8 weeks. Subjects were monitored closely for safety by regular phone calls in between scheduled visits. Two language measures were used, the Test of Problem Solving [TOPS, Zachman et al., 1984] and the Clinical Evaluation of Language Fundamentals-3 [CELF-3, Semel et al., 1995]. The CELF-3 was administered at baseline, week 16, and week 22. The TOPS was completed at all four visits. Because the CELF-3 and TOPS have not been standardized for individuals with DS and the subjects’ language performance was significantly below standard age norms, performance-based comparisons were made with raw scores and age equivalencies. The effect of the medication on language performance was measured by change from baseline performance at the week 8 and week 16 assessments. One subject was excluded from all analyses because of a protocol deviation in administered dosage. No patient experienced serious adverse effects or withdrew from the study. Performance comparisons (completed by repeated measure t-tests) were based on a total n of 6 (five subjects for the baseline vs. week 8 TOPS comparison). Due to the preliminary and exploratory nature of the study, we did not correct for multiple comparisons. P values at or below 0.05 (two-tailed) were viewed as significant. Overall, language performance levels were low. The average TOPS age score was below the 3 years 5 months test basal for all sessions, and the average CELF-3 age score was 4 years 3 months at baseline, and 4 years 7 months at week 16. Essentially no change in language performance with treatment was noted on the TOPS at week 8 (the difference between mean baseline and week 8 scores was <1) and at week 16 (Table I). However, a significant improvement (t = 3.11; P = 0.0265) in overall CELF-3 performance from baseline to week 16 was found (Table I). TABLE I Changes in Raw Score Language Performance From Baseline to 16 Weeks as Measured by the Test of Problem Solving (TOPS) and the Clinical Evaluation of Language Fundamentals (CELF)-3 Additional analyses of the expressive and receptive components of the CELF-3 Total Language Score showed a statistically significant gain of 5 points in expressive language performance (t = 3.14; P = 0.0256) and a similar gain of 4.5 points (approaching statistical significance) in receptive language performance (t = 2.55; P = 0.0513). A review of subject performance on individual expressive and receptive language subtests of the CELF-3 revealed that the largest improvements were made on the word structure and sentence structure subtests. As we noted in our adult study [Heller et al., 2003], these findings should be viewed as preliminary and interpreted with caution because of methodological limitations such as an extremely small sample size, lack of power for formal statistical control, repeated comparisons across a relatively short time span (16 weeks), and the lack of an untreated control group. Our primary finding, which is consistent with the results of our two adult studies, was an improvement in selective aspects of language performance (particularly aspects of expressive language) in children with DS following donepezil therapy. This result is noteworthy in the context of similar findings of language improvement in autistic children treated with two different cholinesterase inhibitors, donepezil hydrochloride [Chez et al., 2000, 2001] and rivastigmine [Chez et al., 2004]. Taken together the results of our work with individuals with DS and Chez’s studies of individuals with autism suggest a relationship between language performance and the cholinergic system that extends across syndromes and that cholinergic therapy is a potential treatment for language impairment in children and adults with significant developmental delays.

Carrier testing in fragile X syndrome: Effect on self‐concept

The purpose of the study was to explore self-concept in women at risk for inheriting the fragile X mutation. Time 1 measures were obtained prior to carrier testing and Time 2 measures were collected approximately 5 months after learning carrier status. The sample consisted of 42 women from 17 families. Measures included the Tennessee Self-Concept Scale (TSCS), the fragile X Visual Analog Scale (VAS), and a structured interview. The TSCS provided a global measure of self-concept and the fragile X VAS and structured interview provided a contextual measure of self related to carrier status. Results indicated that there were no differences initially between carriers and noncarriers and no change from Time 1 to Time 2 on the TSCS. Analysis of the Time 1 fragile X VAS means for the total sample found a reduction in positive feelings about self. Analysis of the Time 2 fragile X VAS found that noncarriers reported improvement in feelings about self, with no change in feelings about self found in the carriers. Responses from the structured interview indicated that the feelings regarding self in the context of genetic testing are not related to global self-concept, but result from concerns regarding the implications of a positive carrier test for themselves and their families. This information highlights areas related to carrier testing that warrant further investigation and may ultimately result in modifications to the genetic counseling.

Longitudinal study of the carrier testing process for fragile X syndrome: Perceptions and coping

This paper reports the results of a longitudinal study of women at-risk to inherit the fragile X mutation. It addresses 1) how upsetting the women perceived their carrier information to be, 2) how serious a problem they perceive fragile X syndrome to be, and 3) descriptions of feelings about the carrier testing process. The study sample consisted of 42 women (20 carriers and 22 noncarriers). There were two measurement times (just prior to carrier testing and after learning actual carrier status). The measures used were a Fragile X Visual Analog Scale and a structured interview. At time 1, being at-risk was reported to be upsetting and fragile X syndrome was perceived to be a serious problem. For the women found to be carriers there was no change from time 1 to time 2 on any of the items. Significant change occurred in the non-carriers. They were significantly less upset at time 2 after receiving the results of their carrier test than at time 1. They also perceived fragile X syndrome to be a more serious problem than they did at time 1 and a more serious problem than the carriers at time 2. Themes found included concerns that carrier status for fragile X syndrome presented a barrier for having healthy biological children and concern for childrens and grandchildrens adaptation to their own carrier status. Coping behaviors were activated to manage the emotions related to these concerns. The coping behaviors identified were minimization, acceptance of the possibility of being a carrier, a sense of being able to deal with the outcome of the carrier test, positive comparison, problem solving, and positive interpretation.

Genetic Counseling-Stress, Coping, and the Empowerment Perspective.

Historically one of the basic foundations of the genetic counseling process has been nondirectiveness; however, its definition and utility continues to be in question. There remains a need to develop genetic counseling interventions in order to qualify, quantify, measure, and enhance the genetic counseling process as well as to delineate the complex interactions of education and counseling that occur. We propose a framework for genetic counseling interventions utilizing an empowerment perspective and Lazarus and Folkmans adaptation of the theory of stress and coping. This model frames the genetic counseling process as one that promotes the autonomy of the individual by providing the individual with the tools required to make their own decisions and enhances coping and adjustment to the outcome of those decisions through control and mastery.

Not the End of the Odyssey: Parental Perceptions of Whole Exome Sequencing (WES) in Pediatric Undiagnosed Disorders

Due to the lack of empirical information on parental perceptions of primary results of whole exome sequencing (WES), we conducted a retrospective semi-structured interview with 19 parents of children who had undergone WES. Perceptions explored during the interview included factors that would contribute to parental empowerment such as: parental expectations, understanding of the WES and results, utilization of the WES information, and communication of findings to health/educational professionals and family members. Results of the WES had previously been communicated to families within a novel framework of clinical diagnostic categories: 5/19 had Definite diagnoses, 6/19 had Likely diagnoses, 3/19 had Possible diagnosis and 5/19 had No diagnosis. All parents interviewed expressed a sense of duty to pursue the WES in search of a diagnosis; however, their expectations were tempered by previous experiences with negative genetic testing results. Approximately half the parents worried that a primary diagnosis that would be lethal might be identified; however, the hope of a diagnosis outweighed this concern. Parents were accurately able to summarize their child’s WES findings, understood the implications for recurrence risks, and were able to communicate these findings to family and medical/educational providers. The majority of those with a Definite/Likely diagnosis felt that their child’s medical care was more focused, or there was a reduction in worry, despite the lack of a specific treatment. Irrespective of diagnostic outcome, parents recommended that follow-up visits be built into the process. Several parents expressed a desire to have all variants of unknown significance (VUS) reported to them so that they could investigate these themselves. Finally, for some families whose children had a Definite/Likely diagnosis, there was remaining frustration and a sense of isolation, due to the limited information that was available about the diagnosed rare disorders and the inability to connect to other families, suggesting that for families with rare genetic disorders, the diagnostic odyssey does not necessarily end with a diagnosis. Qualitative interviewing served a meaningful role in eliciting new information about parental motivations, expectations, and knowledge of WES. Our findings highlight a need for continued communication with families as we navigate the new landscape of genomic sequencing.

Three successful pregnancies through dietary management of fructose-1,6-bisphosphatase deficiency

SummaryFructose-1,6-bisphosphatase (FBPase) deficiency (OMIM 229700) has been characterized as the cause of life-threatening hypoglycaemia and lactic acidaemia following prolonged fasting. The patient, an adult African-American woman, presented during the second trimester of her first pregnancy with recurrent episodes of lactic acidaemia and hypoglycaemia. She had recently been admitted to a nearby intensive care unit after presentation with profound hypoglycaemia and lactic acidosis, and was found to be pregnant. The history was remarkable for approximately 30 hospitalizations for hypoglycaemia and acidosis. She had previously undergone liver biopsy at another centre and was diagnosed with a ‘glycogen storage disease’ although no enzyme testing had been done for confirmation. Based on clinical symptoms, a diagnosis of FBPase deficiency was accomplished through gene sequencing, which revealed homozygosity for a panethnic, common mutation, 960/961insG in exon 7. The availability of mutation testing facilitated the confirmation of FBPase deficiency in this patient, obviating liver biopsy for enzyme activity confirmation. The patient underwent three successful pregnancies by strict compliance with dietary management, including nocturnal uncooked cornstarch to manage hypoglycaemia. The pregnancies were complicated by mild gestational diabetes, increased cornstarch requirements, and hypoglycaemia at the time of discharge from the hospital. The three infants had normal birth weights and experienced no complications during the neonatal period. The patient subsequently developed sensorineural hearing loss and early-onset cognitive impairment, despite compliance with the monitoring and treatment of hypoglycaemia. The experience with multiple pregnancies in this FBPase-deficient patient provides insight into the management of hypoglycaemia in inherited disorders of gluconeogenesis.

A window into living with an undiagnosed disease: illness narratives from the Undiagnosed Diseases Network

AbstractBackgroundPatients’ stories of their illnesses help bridge the divide between patients and providers, facilitating more humane medical care. Illness narratives have been classified into three types: restitution (expectation of recovery), chaos (suffering and loss), and quest (unexpected positive effect from illness). Undiagnosed patients have unique illness experiences and obtaining their narratives would provide insights into the medical and emotional impact of living with an undiagnosed illness. Adults and children with undiagnosed diseases apply to be evaluated by the Undiagnosed Diseases Network (UDN). Written illness narratives from 40 UDN applicants, including 20 adult probands who applied for themselves and 20 parents who applied for their children, were analyzed for: 1) narrative content and 2) narrative type.ResultsNarrative content: could be grouped into three themes: 1) Expectations of the UDN: the majority felt they had no further healthcare options and hoped the UDN would provide them with a diagnosis, with the adults expecting to return to their previously healthy life and the parents wanting information to manage their child’s healthcare. 2) Personal medical information: the narratives reported worsening of symptoms and some offered opinions regarding the cause of their illness. The proband narratives had few objective findings, while parental narratives had detailed objective information. 3) Experiences related to living with their undiagnosed illness: frustration at being undiagnosed was expressed. The adults felt they had to provide validation of their symptoms to providers, given the lack of objective findings. The parents worried that something relevant to their child’s management was being overlooked. Narrative type: All the narratives were of the chaos type, but for different reasons, with the probands describing loss and suffering and the parents expressing fear for their child’s future. The parental narratives also had elements of restitution and quest, with acceptance of “a new normal”, and an emphasis on the positive aspects of their child’s illness which was absent from the probands.ConclusionsThese narratives illustrate the chaos that coexists with being undiagnosed. The differences between the proband and parental narratives suggest that these two groups have different needs that need to be considered during their evaluation and management.