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The increased use of next-generation sequencing has expanded our understanding of the involvement and prevalence of mosaicism in genetic disorders. We describe a total of eleven cases: nine in which mosaic variants detected by genome sequencing (GS) and/or targeted gene panels (TGPs) were considered to be causative for the proband's phenotype, and two of apparent parental mosaicism. Variants were identified in the following genes: PHACTR1, SCN8A, KCNT1, CDKL5, NEXMIF, CUX1, TSC2, GABRB2, and SMARCB1. In addition, we identified one large duplication including three genes, UBE3A, GABRB3, and MAGEL2, and one large deletion including deletion of ARFGAP1, EEF1A2, CHRNA4, and KCNQ2. All patients were enrolled in the NYCKidSeq study, a research program studying the communication of genomic information in clinical care, as well as the clinical utility and diagnostic yield of GS for children with suspected genetic disorders in diverse populations in New York City. We observed variability in the correlation between reported variant allele fraction and the severity of the patient's phenotype, although we were not able to determine the mosaicism percentage in clinically relevant tissue(s). Although our study was not sufficiently powered to assess differences in mosaicism detection between the two testing modalities, we saw a trend toward better detection by GS as compared with TGP testing. This case series supports the importance of mosaicism in childhood-onset genetic conditions and informs guidelines for laboratory and clinical interpretation of mosaic variants detected by GS.

Rare genetic disorders affect as many as 3%-5% of all babies born. Approximately 10,000 such disorders have been identified or hypothesized to exist. Treatment is supportive except in a limited number of instances where specific therapies exist. Development of new therapies has been hampered by at least two major factors: difficulty in diagnosing diseases early enough to enable treatment before irreversible damage occurs, and the high cost of developing new drugs and getting them approved by regulatory agencies. Whole-genome sequencing (WGS) techniques have become exponentially less expensive and more rapid since the beginning of the human genome project, such that return of clinical data can now be achieved in days rather than years and at a cost that is comparable to other less expansive genetic testing. Thus, it is likely that WGS will ultimately become a mainstream, first-tier NBS technique at least for those disorders without appropriate high-throughput functional tests. However, there are likely to be several steps in the evolution to this end. The clinical implications of these advances are profound but highlight the bottlenecks in drug development that still limit transition to treatments. This article summarizes discussions arising from a recent National Institute of Health conference on nucleic acid therapy, with a focus on the impact of WGS in the identification of diagnosis and treatment of rare genetic disorders.

Rare genetic disorders affect as many as 3%-5% of all babies born. Approximately 10,000 such disorders have been identified or hypothesized to exist. Treatment is supportive except in a limited number of instances where specific therapies exist. Development of new therapies has been hampered by at least two major factors: difficulty in diagnosing diseases early enough to enable treatment before irreversible damage occurs, and the high cost of developing new drugs and getting them approved by regulatory agencies. Whole-genome sequencing (WGS) techniques have become exponentially less expensive and more rapid since the beginning of the human genome project, such that return of clinical data can now be achieved in days rather than years and at a cost that is comparable to other less expansive genetic testing. Thus, it is likely that WGS will ultimately become a mainstream, first-tier NBS technique at least for those disorders without appropriate high-throughput functional tests. However, there are likely to be several steps in the evolution to this end. The clinical implications of these advances are profound but highlight the bottlenecks in drug development that still limit transition to treatments. This article summarizes discussions arising from a recent National Institute of Health conference on nucleic acid therapy, with a focus on the impact of WGS in the identification of diagnosis and treatment of rare genetic disorders.CASE VIGNETTEIn 2017, Ipek (her name is used with permission), an apparently healthy baby girl, was born, but newborn screening (NBS) returned a result of concern: a low T-cell Receptor Excision Circle (TREC) count, raising the possibility immunodeficiency. Her ensuing medical evaluation disclosed no signs of severe combined immune deficiency, the usual target of this screening, but unexpectedly pointed to a different diagnosis: ataxia telangiectasia (A-T), a rare and progressive neurodegenerative disorder. In A-T, pathogenic variants in the ATM gene impair the cell's ability to respond to DNA damage, causing the cerebellum to begin to shrink starting in early childhood. The usual course of the disease includes development of symptoms by age five with development of clumsiness and incoordination. By their teenage years, the abilities to walk, talk, swallow, and coordinate her eye movements are lost. She would likely die as a young adult.No treatments for A-T exist. One of the challenges is that most children are diagnosed only after neurologic symptoms emerge, after significant degeneration has already occurred. But because Ipek was diagnosed at such a young age, she could be enrolled in an investigational trial before major neuronal loss. At age two, Ipek began receiving a series of intrathecal injections of an antisense oligonucleotide, designed by Boston Children's Hospital to suppress the effects of an abnormal splice site created by one of her pathogenic ATM variants (Yu lab, manuscript in review). This therapy promises her an improved long-term outcome that would otherwise have been impossible.In an age burgeoning with promising research studies for rare genetic diseases, this case underscores the importance of early screening for access to investigational trials. Early screening with whole-genome sequencing (WGS) can unlock opportunities for genetically targeted or other experimental therapies, such as the mutation-specific therapy designed for Ipek. For instance, 10%-15% of individuals with A-T have been shown to have splice mutations that could make them eligible for treatment with a splice-modulating ASO (and two-thirds of these cases are only detectable via WGS because they involve deep intronic variants and/or structural genomic rearrangements). In the future, early WGS may unlock opportunities for additional targeted therapies like nonsense readthrough or RNA or genome editing.

Liver transplantation is an effective therapeutic option for a variety of inborn errors of metabolism. This approach can significantly improve the quality of life of patients who suffer from severe disease manifestations and/or life-threatening metabolic decompensations despite medical/dietary management. Due to the significant risks for systemic complications from surgical stressors, careful perioperative management is vital. Even after liver transplantation, some disorders require long-term dietary restriction, medical management, and monitoring of metabolites. Successful liver transplant for these complex disorders can be achieved with disease and patient-specific strategies using a multidisciplinary approach. In this article, we review indications, complications, perioperative management and long-term follow up recommendations for inborn errors of metabolism that are treatable with liver transplantation.

Personal genome sequencing is increasingly utilized by healthy individuals for predispositional screening and other applications. However, little is known about the impact of ‘genomic counseling’ on informed decision-making in this context. Our primary aim was to compare measures of participants’ informed decision-making before and after genomic counseling in the HealthSeq project, a longitudinal cohort study of individuals receiving personal results from whole genome sequencing (WGS). Our secondary aims were to assess the impact of the counseling on WGS knowledge and concerns, and to explore participants’ satisfaction with the counseling. Questionnaires were administered to participants (n = 35) before and after their pre-test genomic counseling appointment. Informed decision-making was measured using the Decisional Conflict Scale (DCS) and the Satisfaction with Decision Scale (SDS). DCS scores decreased after genomic counseling (mean: 11.34 before vs. 5.94 after; z = −4.34, p < 0.001, r = 0.52), and SDS scores increased (mean: 27.91 vs. 29.06 respectively; z = 2.91, p = 0.004, r = 0.35). Satisfaction with counseling was high (mean (SD) = 26.91 (2.68), on a scale where 6 = low and 30 = high satisfaction). HealthSeq participants felt that their decision regarding receiving personal results from WGS was more informed after genomic counseling. Further research comparing the impact of different genomic counseling models is needed.

Objective Therapeutic intraarticular injections are used in the management of hip osteoarthritis (OA). Some studies suggest that their use increases the risk of infection and subsequent revision surgery after primary total hip arthroplasty (THA), while others do not. We undertook this study to clarify the relationship between prior intraarticular injection and the risk of complication in a subsequent primary THA. Methods In a cohort of patients with hip OA who underwent a primary elective THA between 2002 and 2009, we identified those who received ≥1 intraarticular injection performed by a radiologist in the 5 years preceding their THA. Multivariable Cox proportional hazards models were used to determine the relationship between receipt of a presurgical injection (no injection, 1–5 years prior to THA, or

L-Carnitine (LC) administration has been recommended for specific indications in dialysis patients, including epoetin-resistant anemia, intradialytic hypotension, cardiomyopathy, fatigue, muscle weakness, and exercise performance; it may ameliorate insulin resistance, inflammation, and protein wasting. Use of LC for anemia and intradialytic hypotension has been approved for reimbursement by the Centers for Medicare and Medicaid Services. Yet, the data to support these recommendations are inadequate and have not been bolstered over several decades. LC administration continues to appeal to nephrologists because its use in dialysis patients has an attractive rationale, it addresses problems that persist despite dialysis, it is safe, and the existing literature does not refute its use. Nevertheless, definitive trials to justify LC administration have not been conducted and are increasingly unlikely to be funded. In an era of shrinking resources and bundling of dialysis services, the use of LC in dialysis patients will, appropriately, diminish.

Niemann-Pick disease (NPD) due to acid sphingomyelinase deficiency is a lipid storage disease resulting from the accumulation of sphingomyelin, predominantly within cells of the monocyte-macrophage system. In contrast to other lysosomal storage disorders, skeletal involvement in NPD has not been systematically studied. Pediatric and adult NPD-B patients underwent medical histories and physical examinations, DEXA scans to measure bone mineral content (BMC), and bone mineral density (BMD) and computed tomography scan or MRI of the abdomen for spleen volume. Z and/or T scores were calculated for the DEXA results. For the pediatric patients adjusted mean BMC (g) and BMD (g/cm2) of the lumbar spine, hip, and femoral neck was compared to control subjects. For determination of the relationship between spleen volume and lumbar spine BMD Z score, linear correlation analyses were performed. Lumbar spine Z scores for pediatric patients ranged from 0.061 to -4.879. Statistically significant decreases were observed for the adjusted mean BMC and BMD at the lumbar spine, hip, and femoral neck between the pediatric NPD-B cohort and control subjects. Most NPD-B adults were osteopenic or osteoporotic at one or more sites according the WHO classification of BMD. In NPD-B patients, the degree of splenomegaly was inversely correlated with lumbar spine BMD Z scores. Skeletal involvement is a common and previously unrecognized manifestation of NPD-B. The association between splenomegaly and BMD lends further support to spleen size as an indicator of disease severity.

Patients with HT-1 can develop progressive liver disease and have a high incidence of HCC. LT is indicated in patients with fulminant liver failure, HCC or decompensated chronic liver disease refractory to NTBC. To determine the need for LT and outcomes after LT in children with HT-1. Children with HT-1 who had LT between 10/1987 and 5/2008 were identified from the UNOS database. Of 11,467 children in the UNOS database, 125 (1.1%) required LT secondary to HT-1. Mean age at LT was two and half yr (s.d. ± 3.6 yr). Mean age at LT during the first 10 yr of the study (1.82, s.d. ± 2.86 yr) was significantly lower than in the last decade (3.70, s.d. ± 4.42 yr), p = 0.01. Nearly half of the patients (58, 46.4%) were transplanted between 1988 and 1992. Overall, one- and five-yr patient survival was 90.4% and 90.4%, respectively. LT is a valuable option for children with HT-1 with fulminant liver failure or when medical treatment fails. The rate of LT for children with HT-1 has decreased and age at transplant increased over the last decade most probably reflecting the effect of early diagnosis and treatment with NTBC.

Obesity has been identified as a risk factor for the development of hip and knee osteoarthritis (OA) and may play a role in exacerbating existing disease. Therefore, we hypothesized that obese patients would present for hip and knee replacement surgery at a younger age than nonobese patients. From our registry, we performed a cross-sectional study of 841 hip and 804 knee replacement patients. Patients were categorized by BMI ≤ 25 kg/m(2), 25.1-29.9 kg/m(2), 30-34.9 kg/m(2), and ≥ 35 kg/m(2). Linear regression modeling was used to examine the relationship between BMI and age at surgery. Hip and knee replacement patients' mean age at surgery was 7.1 and 7.9 years younger, respectively, if their BMI was ≥ 35 kg/m(2) when compared to patients with a BMI ≤ 25 kg/m(2) (P = 0.002). BMI was a significant independent (of gender, Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, surgeon, and comorbidity) predictor of age at knee replacement (P < 0.05). WOMAC scores were significantly worse preoperatively in patients with a BMI ≥ 35 kg/m(2) compared to those with a BMI ≤ 25 kg/m(2) (P < 0.05). Our study indicates that obese patients, especially those with a BMI ≥ 35 kg/m(2), presented for and underwent joint replacement surgery at a younger age as compared to nonobese patients.

Phenylketonuria (PKU) is an inherited metabolic disease characterized by phenylalanine (Phe) accumulation, which can lead to neurocognitive and neuromotor impairment. Sapropterin dihydrochloride, an FDA-approved synthetic formulation of tetrahydrobiopterin (6R-BH4, herein referred to as sapropterin) is effective in reducing plasma Phe concentrations in patients with hyperphenylalaninemia due to tetrahydrobiopterin (BH4)-responsive PKU, offering potential for improved metabolic control. Eighty patients, ≥8 years old, who had participated in a 6-week, randomized, placebo-controlled study of sapropterin, were enrolled in this 22-week, multicenter, open-label extension study comprising a 6-week forced dose-titration phase (5, 20, and 10 mg/kg/day of study drug consecutively for 2 weeks each), a 4-week dose-analysis phase (10 mg/kg/day), and a 12-week fixed-dose phase (patients received doses of 5, 10, or 20 mg/kg/day based on their plasma Phe concentrations during the dose titration). Dose-dependent reductions in plasma Phe concentrations were observed in the forced dose-titration phase. Mean (SD) plasma Phe concentration decreased from 844.0 (398.0) µmol/L (week 0) to 645.2 (393.4) µmol/L (week 10); the mean was maintained at this level during the study's final 12 weeks (652.2 [382.5] µmol/L at week 22). Sixty-eight (85%) patients had at least one adverse event (AE). All AEs, except one, were mild or moderate in severity. Neither the severe AE nor any of the three serious AEs was considered related to sapropterin. No AE led to treatment discontinuation. Sapropterin is effective in reducing plasma Phe concentrations in a dose-dependent manner and is well tolerated at doses of 5–20 mg/kg/day over 22 weeks in BH4-responsive patients with PKU. © 2008 Wiley-Liss, Inc.

Recent studies of ADHD implicate well-defined neuroanatomical networks and neurochemical pathways in its pathophysiological basis. Considerable attention has focused on the role of anterior and superior frontal regions and portions of the basal ganglia, including the caudate nucleus and globus pallidus. This paper reviews a growing literature suggesting differential involvement of right hemisphere mechanisms specialized for behavioral regulation and attention. Supportive data are drawn from neuropsychology, neuroanatomy, and neurochemistry. In addition, three cases are presented that illustrate the complex role of right hemisphere dysfunction in adult manifestations of ADHD. We suggest that the pleomorphic presentations of ADHD can be understood in terms of a spectrum of disturbances in overlapping neural regions, especially involving frontal and parietal areas of the right hemisphere and their connections to subcortical structures (including the striatum, limbic system and diencephalic nuclei).

This concluding paper raises some final questions and issues that the authors feel should receive more emphasis in future research on ADHD in adults. One significant problem for our field is the upward extension of child-based models and approaches without proper adaptation to adults. With adults differing patterns of comorbidity and symptom heterogeneity pose new conceptual, diagnostic, and treatment challenges. As an illustration, we review ten common presenting complaints in adults and their link to the underlying core ADHD deficits of hyperkinesis, inattention, and impulsivity. While these core symptoms are often overt problems in children, in adults subtler executive dysfunction appears. Even though the growing consensus is that ADHD is a disorder of executive functions (EF), the details of the EF/ADHD connection remain unclear and may be far more complex in adults. That complexity is mirrored in the widening anatomic representation of EF, extending beyond the frontal lobes into the subcortex and other nonfrontal regions. More research will be needed to follow the developmental trajectory of executive dysfunction in ADHD over the life cycle and tie this to the developmental neuropsychology of EF. Psychosocial context and nongenetic familial influence are also critical variables that need greater consideration when characterizing and measuring ADHD symptoms in adults. Finally, until we have reached consensus on adult subject selection, we may not be able to enhance diagnostic rigor or expand our conceptual framework for understanding the underlying pathophysiology of ADHD in adults.

The neuropathology underlying ADHD most consistently points to dysfunction in corticostriatal pathways—leading to inactivation, or insufficient engagement, of frontal and prefrontal lobes. By implication there may be functional disconnection between the anterior and posterior higher cortical regions, instead of a fixed dysfunction in either one. Given this premise, reconnection of these systems via cognitive interventions constitutes a logical remedial approach in the treatment of ADHD, which this paper introduces. In particular, a hybrid model is developed which proposes integration of existing psychodynamic, cognitive, and neuropsychological interventions. An organizing theme is expansion of metacognitive understanding through these procedures, powerfully exemplified via use of metaphor in clinical vignettes.

Attention-Deficit Hyperactivity Disorder (ADHD) is a common, genetically transmitted neurological disorder, with onset in childhood, probably mediated by decreased brain dopaminergic functioning. The first author was one of the earliest to describe the persistence of symptoms into adulthood. Prevalence and natural history data suggest that of the 3 to 10% of children diagnosed with ADHD, one- to two-thirds (somewhere between 1 and 6% of the general population) continue to manifest appreciable ADHD symptoms into adult life. This paper describes how ADHD in adults can be readily diagnosed and treated, despite resembling or coexisting with other psychiatric disorders. The Wender Utah diagnostic criteria address adult characteristics of the disorder. Informant and patient interviews and rating scales are used to determine the psychiatric status of the patient as a child, make a retroactive diagnosis of childhood ADHD, and establish the current diagnosis of the adult. Stringent diagnosis is key to determining effective treatment. Dopamine agonist stimulant medications appear to be the most effective in treating ADHD. About 60% of patients receiving stimulant medication showed moderate-to-marked improvement, as compared with 10% of those receiving placebo. The core symptoms of hyperactivity, inattention, mood lability, temper, disorganization, stress sensitivity, and impulsivity have been shown to respond to treatment with stimulant medications. Non-dopaminergic medications, such as the tricyclic antidepressants and SSRIs have generally not been useful in adults with ADHD in the absence of depression or dysthymia. Pemoline is no longer approved for use in these patients, despite early favorable reports. Appropriate management of adult patients with ADHD is multimodal. Psychoeducation, counseling, supportive problem-directed therapy, behavioral intervention, coaching, cognitive remediation, and couples and family therapy are useful adjuncts to medication management. Concurrent supportive psychosocial treatment or polypharmacy may be useful in treating the adult with comorbid ADHD.

Methylmalonic acidaemia is an inborn error of metabolism characterized by recurrent episodes of life-threatening ketoacidosis. With improved and intensive treatment, these patients are living into adulthood, but many experience late-onset disease complications such as chronic renal failure, chronic pancreatitis and osteopenia. We report the successful delivery of a healthy baby to a 20-year-old woman with vitamin B12-unresponsive methylmalonic acidaemia who has these late-onset manifestations of the disease and had plasma methylmalonic acid concentrations of 1900 mumol/L during the first trimester of pregnancy.

The finding of extensive lytic lesions in the mandible of a 19-year-old Ashkenazi Jewish woman led to the diagnosis of Type 1 Gaucher disease. She had extensive skeletal involvement, marked hepatosplenomegaly, and deficient acid β-glucosidase activity. Mutation analysis identified heteroallelism for acid β-glucosidase mutations N370S and P401L, the latter being a novel missense mutation in exon 9. Expression of the P401L allele resulted in an enzyme with a reduced catalytic activity (specific activity based on cross-reacting immunological material ∼0.21), which was similar to that of the mild N370S mutant enzyme. The expression studies predicted a mild phenotype for the proposita's N370S/P401L genotype which was inconsistent with her severe diffuse skeletal disease and organ involvement. Since lytic mandibular lesions may be complicated by osteomyelitis, pathologic fracture, and tooth loss, regular dental assessments in Type 1 Gaucher patients should be performed. Am. J. Med. Genet. 84:334–339, 1999. © 1999 Wiley-Liss, Inc.

This study examined worry in elementary school aged children and its relation to anxiety. The study also examined whether parameters of excessive or dysfunctional worry could be delineated. Children from second through sixth grades (ages 7-12 years) were interviewed using a structured approach and completed several child anxiety measures. Parameters of worry assessed included: number of worries, areas of worry, intensity of worries, and perceptions of the frequency of worry events. Findings revealed few age-related differences but found that girls reported more worries than boys and that African-Americans reported more worries than white or Hispanic children. The three most common areas of worry involved School, Health, and Personal Harm. Anxiety was significantly associated with worry, providing empirical support for a link between these two constructs. Worry parameters, especially number and intensity of worries, could differentiate high and low anxious children in a normal school sample. Implications of these findings for understanding the role of worry in childhood anxiety are discussed.

We describe 5 individuals (from three separate families) with a progressive neurological disorder characterized by sensorimotor peripheral polyneuropathy, cranial neuropathies (external ophthalmoplegia, deafness), and the syndrome of chronic intestinal pseudo-obstruction. Magnetic resonance imaging showed widespread abnormality of the cerebral and cerebellar white matter in the 2 patients studied. Autopsy examination in 3 revealed widespread endoneurial fibrosis and demyelination in the peripheral nervous system, possibly secondary to axonal atrophy, and poorly defined changes in cerebral white matter (leukoencephalopathy). The cranial nerves and spinal roots were less severely involved and the neurons in the brainstem and spinal cord were intact. The fatal gastrointestinal dysmotility was due to a severe visceral neuropathy. We suggest that these patients manifested a hereditary disorder with distinctive clinical, radiological, and neuropathological features, and propose the acronym POLIP to emphasize the distinctive tetrad of polyneuropathy, ophthalmoplegia, leukoencephalopathy, and intestinal pseudo-obstruction.