[Show abstract][Hide abstract] ABSTRACT: Brainstem disconnection (BD) is a rare posterior fossa abnormality defined by the nearly complete absence of a brainstem segment with the rostral and caudal brainstem portions connected only by a thin cord of tissue. The outcome is poor and the majority of children die within the first 2 months of life without achieving developmental milestones. We report on the cases of two children with BD and a prolonged spontaneous survival. Neither patient required intubation or mechanical ventilation and each survived longer than 2 months (one child died at the age of 8 months, the other is alive at the age of 4.5 years). In addition, patient 1 is the only child with BD reported so far who achieved some developmental milestones. Although the long-term neurodevelopmental outcome of BD remains unfavorable, the expansion of the phenotypic spectrum may be important in terms of counseling.
[Show abstract][Hide abstract] ABSTRACT: In this study, we retrospectively examined the microstructural white matter integrity of children with early- and continuously-treated PKU (N = 36) in relation to multiple indices of phenylalanine (Phe) control over the lifetime. White matter integrity was assessed using mean diffusivity (MD) from diffusion tensor imaging (DTI). Eight lifetime indices of Phe control were computed to reflect average Phe (mean, index of dietary control), variability in Phe (standard deviation, standard error of estimate, % spikes), change in Phe with age (slope), and prolonged exposure to Phe (mean exposure, standard deviation exposure). Of these indices, mean Phe, mean exposure, and standard deviation exposure were the most powerful predictors of widespread microstructural white matter integrity compromise. Findings from the two previously unexamined exposure indices reflected the accumulative effects of elevations and variability in Phe. Given that prolonged exposure to elevated and variable Phe was particularly detrimental to white matter integrity, Phe should be carefully monitored and controlled throughout childhood, without liberalization of Phe control as children with PKU age.
[Show abstract][Hide abstract] ABSTRACT: Study objectives:
For children with trisomy 21, polysomnography at age 4 to assess obstructive sleep disordered breathing (OSDB) is the standard of care. Oximetry alone has been used to screen for disease among children without trisomy 21. This study evaluates the potential usefulness of oximetry scoring in diagnosing OSDB among children with trisomy 21.
A McGill oximetry score from 1 to 4 was derived from a full overnight PSG done on 119 consecutive pediatric subjects with trisomy 21. Most were referred to the sleep laboratory because of suspicion for OSDB. Oximetry scorers were blinded to the child's full PSG and clinical course. Results of the complete PSG were then compared to oximetry scores.
Obstructive apnea-hypopnea index (OAHI) was ≥ 2.5 for 50% of all subjects. Fifty-nine subjects (49.6%) had McGill Score 1 ("inconclusive"); median OAHI was 1.0 (IQR 0.4-3.3). McGill Score was 2 for 43 subjects (36.1%); median OAHI was 4.5 (IQR 1.3-8.8). Seventeen subjects (14.3%) had McGill Scores of 3 or 4; median OAHI was 16.1 (IQR 9.3-45.5, range 2.1 to 101.1). Ten percent of subjects had a considerable number of central events (≥ 2.5 respiratory events/h but OAHI < 2.5), including 7 with McGill Score 2.
In a retrospective cohort of children with trisomy 21, McGill oximetry scores of 3 or 4 reliably identified patients with marked OSDB. The possibility of central apneas causing hypoxemia must be considered in those with McGill Score 2. With these caveats, oximetry screening should be considered when developing streamlined protocols for early intervention to treat OSDB in this population.
Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine 10/2014; 10(12). DOI:10.5664/jcsm.4286 · 3.05 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Fabry disease is a pan-ethnic, progressive, X-linked genetic disorder that commonly presents in childhood and is caused by deficient activity of the lysosomal enzyme alpha-galactosidaseA (α-gal A). Symptoms of Fabry disease in the pediatric population are well described for patients over five years of age; however, data are limited for infancy and early childhood. The purpose of this article is to delineate the age of detection for specific Fabry symptoms in early childhood.
A systematic retrospective analysis of PubMed indexed, peer-reviewed publications and case reports in the pediatric Fabry population was performed to review symptoms in patients reported before 5 years of age.
The most frequently reported symptom in all age groups under 5 years was acroparesthesias/neuropathic pain, reported in 9 children, ranging in age from 2.0-4.0 years. Also notable is the frequency of gastrointestinal issues reported in 6 children aged 1.0-4.1 years of age.
This article finds clear evidence that symptoms can occur in early childhood, before age 5 years. Given early presenting symptoms and the ability to monitor these disease hallmarks, a timely referral to a medical geneticist or other specialty clinician experienced in managing children with Fabry disease is strongly indicated.
Genetics in medicine: official journal of the American College of Medical Genetics 09/2014; 17(5). DOI:10.1038/gim.2014.120 · 7.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Human Herpes Virus type-6 (HHV-6) is a significant cause of the febrile illness roseola infantum in young children. Infection with HHV-6 typically causes a self-limited febrile illness, but occasionally is associated with central nervous system manifestations, including febrile seizures and encephalitis. Host factors associated with severe manifestations of HHV-6-associated neurologic disease remain poorly characterized.
We report two cases of previously healthy young boys with HHV-6-associated encephalitis who developed a progressive, and ultimately fatal, encephalopathy with refractory movement disorder concurrent with acquisition of acute HHV-6 infection. Both children were treated with the antiviral ganciclovir without improvement in their neurologic symptoms, although quantitative HHV-6 PCR of CSF and/or blood confirmed a decline in viral load with treatment. The clinical course in both cases was most consistent with Alpers-Huttenlocher syndrome, given the intractable seizures, developmental regression and, ultimately, death due to liver and renal failure. In support of this, post-mortem analysis identified both children to be compound heterozygotes for mutations in the mitochondrial polymerase γ gene, POLG.
POLG mutations are associated with Alpers-Huttenlocher syndrome, however no prior studies have examined the role of acute HHV-6 infection in these patients presenting with severe neurologic disease. It is possible the POLG mutation phenotype was unmasked and/or exacerbated by HHV-6 infection in these two patients, potentially contributing to a more rapid clinical deterioration. This report provides new insight into a previously unrecognized association between POLG mutations and poor neurologic outcome following HHV-6 infection.
[Show abstract][Hide abstract] ABSTRACT: Hypohidrotic ectodermal dysplasia (HED) is the most prevalent type of ectodermal dysplasia (ED). ED is an umbrella term for a group of syndromes characterized by missing or malformed ectodermal structures, including skin, hair, sweat glands, and teeth. The X-linked recessive (XL), autosomal recessive (AR), and autosomal dominant (AD) types of HED are caused by mutations in the genes encoding ectodysplasin (EDA1), EDA receptor (EDAR), or EDAR-associated death domain (EDARADD). Patients with HED have a distinctive facial appearance, yet a quantitative analysis of the HED craniofacial phenotype using advanced three-dimensional (3D) technologies has not been reported. In this study, we characterized craniofacial morphology in subjects with X-linked hypohidrotic ectodermal dysplasia (XLHED) by use of 3D imaging and geometric morphometrics (GM), a technique that uses defined landmarks to quantify size and shape in complex craniofacial morphologies. We found that the XLHED craniofacial phenotype differed significantly from controls. Patients had a smaller and shorter face with a proportionally longer chin and midface, prominent midfacial hypoplasia, a more protrusive chin and mandible, a narrower and more pointed nose, shorter philtrum, a narrower mouth, and a fuller and more rounded lower lip. Our findings refine the phenotype of XLHED and may be useful both for clinical diagnosis of XLHED and to extend understanding of the role of EDA in craniofacial development.
[Show abstract][Hide abstract] ABSTRACT: ATP-sensitive potassium (KATP ) channels, composed of inward-rectifying potassium channel subunits (Kir6.1 and Kir6.2, encoded by KCNJ8 and KCNJ11, respectively) and regulatory sulfonylurea receptor (SUR1 and SUR2, encoded by ABCC8 and ABCC9, respectively), couple metabolism to excitability in multiple tissues. Mutations in ABCC9 cause Cantú syndrome, a distinct multi-organ disease, potentially via enhanced KATP channel activity. We screened KCNJ8 in an ABCC9 mutation-negative patient who also exhibited clinical hallmarks of Cantú syndrome (hypertrichosis, macrosomia, macrocephaly, coarse facial appearance, cardiomegaly, and skeletal abnormalities). We identified a de novo missense mutation encoding Kir6.1[p.Cys176Ser] in the patient. Kir6.1[p.Cys176Ser] channels exhibited markedly higher activity than wild-type channels, as a result of reduced ATP sensitivity, whether co-expressed with SUR1 or SUR2A subunits. Our results identify a novel causal gene in Cantú syndrome, but also demonstrate that the cardinal features of the disease result from gain of KATP channel function, not from Kir6-independent SUR2 function. This article is protected by copyright. All rights reserved.
Human Mutation 07/2014; 35(7). DOI:10.1002/humu.22555 · 5.14 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Adolescent idiopathic scoliosis (AIS) causes spinal deformity in 3% of children. Despite a strong genetic basis, few genes
have been associated with AIS and the pathogenesis remains poorly understood. In a genome-wide rare variant burden analysis
using exome sequence data, we identified fibrillin-1 (FBN1) as the most significantly associated gene with AIS. Based on these results, FBN1 and a related gene, fibrillin-2 (FBN2), were sequenced in a total of 852 AIS cases and 669 controls. In individuals of European ancestry, rare variants in FBN1 and FBN2 were enriched in severely affected AIS cases (7.6%) compared with in-house controls (2.4%) (OR = 3.5, P = 5.46 × 10−4) and Exome Sequencing Project controls (2.3%) (OR = 3.5, P = 1.48 × 10−6). Scoliosis severity in AIS cases was associated with FBN1 and FBN2 rare variants (P = 0.0012) and replicated in an independent Han Chinese cohort (P = 0.0376), suggesting that rare variants may be useful as predictors of curve progression. Clinical evaluations revealed
that the majority of AIS cases with rare FBN1 variants do not meet diagnostic criteria for Marfan syndrome, though variants are associated with tall stature (P = 0.0035) and upregulation of the transforming growth factor beta pathway. Overall, these results expand our definition of
fibrillin-related disorders to include AIS and open up new strategies for diagnosing and treating severe AIS.
Human Molecular Genetics 05/2014; 23(19). DOI:10.1093/hmg/ddu224 · 6.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: For pregnant women with phenylketonuria (PKU), maintaining blood phenylalanine (Phe) < 360 μmol/L is critical due to the toxicity of elevated Phe to the fetus. Sapropterin dihydrochloride (sapropterin) lowers blood Phe in tetrahydrobiopterin (BH4) responsive patients with PKU, in conjunction with a Phe-restricted diet, but clinical evidence supporting its use during pregnancy is limited. As of June 3, 2013, the Maternal Phenylketonuria Observational Program (PKU MOMS) sub-registry contained data from 21 pregnancies – in women with PKU who were either treated with sapropterin before (N = 5) or during (N = 16) pregnancy. Excluding data for spontaneous abortions (N = 4), the data show that the mean of median blood Phe [204.7 ± 126.6 μmol/L (n = 14)] for women exposed to sapropterin during pregnancy was 23% lower, and had a 58% smaller standard deviation, compared to blood Phe [267.4 ± 300.7 μmol/L (n = 3)] for women exposed to sapropterin prior to pregnancy. Women on sapropterin during pregnancy experienced fewer blood Phe values above the recommended 360 μmol/L threshold. When median blood Phe concentration was < 360 μmol/L throughout pregnancy, 75% (12/16) of pregnancy outcomes were normal compared to 40% (2/5) when median blood Phe was > 360 μmol/L. Severe Adverse Events identified by the investigators as possibly related to sapropterin use were premature labor (N = 1) and spontaneous abortion (N = 1) for the women and hypophagia for the offspring [premature birth (35w4d), N = 1]. One congenital malformation (cleft palate) of unknown etiology was reported as unrelated to sapropterin. Although there is limited information regarding the use of sapropterin during pregnancy, these sub-registry data show that sapropterin was generally well-tolerated and its use during pregnancy was associated with lower mean blood Phe. Because the teratogenicity of elevated maternal blood Phe is without question, sapropterin should be considered as a treatment option in pregnant women with PKU who cannot achieve recommended ranges of blood Phe with dietary therapy alone.
[Show abstract][Hide abstract] ABSTRACT: Mutations in GLI2 have been associated with holoprosencephaly (HPE), a neuroanatomic anomaly resulting from incomplete cleavage of the developing forebrain, and an HPE-like phenotype involving pituitary anomalies and polydactyly.
To characterise the genotypic and phenotypic findings in individuals with GLI2 variants and clarify clinical findings in individuals with loss-of-function mutations.
Through the National Institutes of Health and collaborating centres, ∼400 individuals with HPE spectrum disorders, endocrine disorders or craniofacial anomalies were screened for GLI2 mutations. Results were combined with all published cases. We compared the clinical and molecular features of individuals with truncating mutations to individuals with variants of unknown significance (defined as not resulting in protein truncation, reported in normal controls and/or deemed unlikely to be pathogenic by functional prediction software).
112 individuals with variants in GLI2 were identified, with 43 having truncating mutations. Individuals with truncating mutations were more likely to have both pituitary anomalies and polydactyly versus those with variants of unknown significance (p<0.0001 by Fisher's exact test); only 1 of 43 had frank HPE. These individuals were more likely to have recognised penetrance (polydactyly or pituitary anomalies or both) than those without truncating mutations (p=0.0036 by Fisher's exact test). A common facial phenotype was seen in individuals (with midface hypoplasia, cleft lip/palate and hypotelorism) with truncating mutations.
Individuals with truncating mutations in GLI2 typically present with pituitary anomalies, polydactyly and subtle facial features rather than HPE. This will be helpful in screening populations for GLI2 mutations and for counselling affected patients.
Journal of Medical Genetics 04/2014; 51(6). DOI:10.1136/jmedgenet-2013-102249 · 6.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Phenylketonuria is an inherited disease caused by impaired activity of phenylalanine hydroxylase, the enzyme that converts phenylalanine to tyrosine, leading to accumulation of phenylalanine and subsequent neurocognitive dysfunction. Phenylalanine ammonia lyase is a prokaryotic enzyme that converts phenylalanine to ammonia and trans-cinnamic acid. We aimed to assess the safety, tolerability, pharmacokinetic characteristics, and efficacy of recombinant Anabaena variabilis phenylalanine ammonia lyase (produced in Escherichia coli) conjugated with polyethylene glycol (rAvPAL-PEG) in reducing phenylalanine concentrations in adult patients with phenylketonuria.
In this open-label, phase 1, multicentre trial, single subcutaneous injections of rAvPAL-PEG were given in escalating doses (0·001, 0·003, 0·010, 0·030, and 0·100 mg/kg) to adults with phenylketonuria. Participants aged 18 years or older with blood phenylalanine concentrations of 600 μmol/L or higher were recruited from among patients attending metabolic disease clinics in the USA. The primary endpoints were safety and tolerability of rAvPAL-PEG. Secondary endpoints were the pharmacokinetic characteristics of the drug and its effect on concentrations of phenylalanine. Participants and investigators were not masked to assigned dose group. This study is registered with ClinicalTrials.gov, number NCT00925054.
25 participants were recruited from seven centres between May 6, 2008, and April 15, 2009, with five participants assigned to each escalating dose group. All participants were included in the safety population. The most frequently reported adverse events were injection-site reactions and dizziness, which were self-limited and without sequelae. Two participants had serious adverse reactions to intramuscular medroxyprogesterone acetate, a drug that contains polyethylene glycol as an excipient. Three of five participants given the highest dose of rAvPAL-PEG (0·100 mg/kg) developed a generalised skin rash. By the end of the study, all participants had developed antibodies against polyethylene glycol, and some against phenylalanine ammonia lyase as well. Drug concentrations peaked about 89-106 h after administration of the highest dose. Treatment seemed to be effective at reducing blood phenylalanine in all five participants who received the highest dose (mean reduction of 54·2% from baseline), with a nadir about 6 days after injection and an inverse correlation between drug and phenylalanine concentrations in plasma. Phenylalanine returned to near-baseline concentrations about 21 days after the injection.
Subcutaneous administration of rAvPAL-PEG in a single dose of up to 0·100 mg/kg was fairly safe and well tolerated in adult patients with phenylketonuria. At the highest dose tested, rAvPAL-PEG reduced blood phenylalanine concentrations. In view of the development of antibodies against polyethylene glycol (and in some cases against phenylalanine ammonia lyase), future studies are needed to assess the effect of repeat dosing.
The Lancet 04/2014; 384(9937). DOI:10.1016/S0140-6736(13)61841-3 · 45.22 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Intragenic copy number variations involving the calmodulin-binding transcription activator 1 (CAMTA1) gene have recently been reported in four unrelated families with intellectual disability (ID), ataxia, behavioral- and cerebellar abnormalities.We report a detailed phenotypic and molecular characterization of three individuals with novel intragenic CAMTA1 deletions from two unrelated families and compare the findings to those of previously reported patients.Our patients had deletions of exons 6-11 and presented with ID, developmental delay (DD), attention deficit hyperactivity disorder (ADHD) and constipation. Two individuals from one family had also unsteady gait. Consistent phenotypes associated with CAMTA1 intragenic rearrangements include ID, speech problems and some dysmorphic features whereas neurobehavioral abnormalities are variable. We did not observe obvious phenotypic differences between patients with in-frame and those with frameshift rearrangements.There is increased evidence that CAMTA1 has a role in brain and cerebellar function. CAMTA1 should be added to the growing list of genes associated with ID/DD, especially when behavioral problems, cerebellar signs, and/or dysmorphism are also present.
[Show abstract][Hide abstract] ABSTRACT: Biallelic mutations of UBE3B have recently been shown to cause Kaufman oculocerebrofacial syndrome (also reported as blepharophimosis-ptosis-intellectual disability syndrome), an autosomal recessive condition characterized by hypotonia, developmental delay, intellectual disability, congenital anomalies, characteristic facial dysmorphic features, and low cholesterol levels. To date, six patients with either missense mutations affecting the UBE3B HECT domain or truncating mutations have been described. Here, we report on the identification of homozygous or compound heterozygous UBE3B mutations in six additional patients from five unrelated families using either targeted UBE3B sequencing in individuals with suggestive facial dysmorphic features, or exome sequencing. Our results expand the clinical and mutational spectrum of the UBE3B-related disorder in several ways. First, we have identified UBE3B mutations in individuals who previously received distinct clinical diagnoses: two sibs with Toriello-Carey syndrome as well as the patient reported to have a "new" syndrome by Buntinx and Majewski in 1990. Second, we describe the adult phenotype and clinical variability of the syndrome. Third, we report on the first instance of homozygous missense alterations outside the HECT domain of UBE3B, observed in a patient with mildly dysmorphic facial features. We conclude that UBE3B mutations cause a clinically recognizable and possibly underdiagnosed syndrome characterized by distinct craniofacial features, hypotonia, failure to thrive, eye abnormalities, other congenital malformations, low cholesterol levels, and severe intellectual disability. We review the UBE3B-associated phenotypes, including forms that can mimick Toriello-Carey syndrome, and suggest the single designation "Kaufman oculocerebrofacial syndrome".
Human Genetics 03/2014; 133(7). DOI:10.1007/s00439-014-1436-2 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: New developments in the treatment and management of phenylketonuria (PKU) as well as advances in molecular testing have emerged since the National Institutes of Health 2000 PKU Consensus Statement was released. An NIH State-of-the-Science Conference was convened in 2012 to address new findings, particularly the use of the medication sapropterin to treat some individuals with PKU, and to develop a research agenda. Prior to the 2012 conference, five working groups of experts and public members met over a 1-year period. The working groups addressed the following: long-term outcomes and management across the lifespan; PKU and pregnancy; diet control and management; pharmacologic interventions; and molecular testing, new technologies, and epidemiologic considerations. In a parallel and independent activity, an Evidence-based Practice Center supported by the Agency for Healthcare Research and Quality conducted a systematic review of adjuvant treatments for PKU; its conclusions were presented at the conference. The conference included the findings of the working groups, panel discussions from industry and international perspectives, and presentations on topics such as emerging treatments for PKU, transitioning to adult care, and the U.S. Food and Drug Administration regulatory perspective. Over 85 experts participated in the conference through information gathering and/or as presenters during the conference, and they reached several important conclusions. The most serious neurological impairments in PKU are preventable with current dietary treatment approaches. However, a variety of more subtle physical, cognitive, and behavioral consequences of even well-controlled PKU are now recognized. The best outcomes in maternal PKU occur when blood phenylalanine (Phe) concentrations are maintained between 120 and 360μmol/L before and during pregnancy. The dietary management treatment goal for individuals with PKU is a blood Phe concentration between 120 and 360μmol/L. The use of genotype information in the newborn period may yield valuable insights about the severity of the condition for infants diagnosed before maximal Phe levels are achieved. While emerging and established genotype-phenotype correlations may transform our understanding of PKU, establishing correlations with intellectual outcomes is more challenging. Regarding the use of sapropterin in PKU, there are significant gaps in predicting response to treatment; at least half of those with PKU will have either minimal or no response. A coordinated approach to PKU treatment improves long-term outcomes for those with PKU and facilitates the conduct of research to improve diagnosis and treatment. New drugs that are safe, efficacious, and impact a larger proportion of individuals with PKU are needed. However, it is imperative that treatment guidelines and the decision processes for determining access to treatments be tied to a solid evidence base with rigorous standards for robust and consistent data collection. The process that preceded the PKU State-of-the-Science Conference, the conference itself, and the identification of a research agenda have facilitated the development of clinical practice guidelines by professional organizations and serve as a model for other inborn errors of metabolism.
[Show abstract][Hide abstract] ABSTRACT: Cornelia de Lange syndrome (CdLS) is a genetically heterogeneous disorder characterized by growth retardation, intellectual disability, upper limb abnormalities, hirsutism, and characteristic facial features. In this study we explored the occurrence of intragenic NIPBL copy number variations (CNVs) in a cohort of 510 NIPBL sequence-negative patients with suspected CdLS. Copy number analysis was performed by custom exon-targeted oligonucleotide array-comparative genomic hybridization and/or MLPA. Whole-genome SNP array was used to further characterize rearrangements extending beyond the NIPBL gene. We identified NIPBL CNVs in 13 patients (2.5%) including one intragenic duplication and a deletion in mosaic state. Breakpoint sequences in two patients provided further evidence of a microhomology-mediated replicative mechanism as a potential predominant contributor to CNVs in NIPBL. Patients for whom clinical information was available share classical CdLS features including craniofacial and limb defects. Our experience in studying the frequency of NIBPL CNVs in the largest series of patients to date widens the mutational spectrum of NIPBL and emphasizes the clinical utility of performing NIPBL deletion/duplication analysis in patients with CdLS.
[Show abstract][Hide abstract] ABSTRACT: A number of studies have revealed significant relationships between cognitive performance and average phenylalanine (Phe) levels in children with phenylketonuria (PKU), but only a few studies have been conducted to examine the relationships between cognitive performance and variability (fluctuations) in Phe levels. In the current study, we examined a variety of indices of Phe control to determine which index best predicted IQ and executive abilities in 47 school-age children with early- and continuously-treated PKU. Indices of Phe control were mean Phe, the index of dietary control, change in Phe with age, and several indices of variability in Phe (standard deviation, standard error of estimate, and percentage of spikes). These indices were computed over the lifetime and during 3 developmental epochs (<5, 5.0-9.9, and ≥10years of age). Results indicated that variability in Phe was generally a stronger predictor of cognitive performance than other indices of Phe control. In addition, executive performance was better predicted by variability in Phe during older than younger developmental epochs. These results indicate that variability in Phe should be carefully controlled to maximize cognitive outcomes and that Phe control should not be liberalized as children with PKU age.