To the Editor:
In the Case Record, Hogan et al. (Feb. 14 issue)
1
describe a patient with pernicious anemia and recommend the indefinite use of intramuscular vitamin B
12
for cobalamin deficiency. ...Oral or sublingual vitamin B
12
can be effective in the treatment of pernicious anemia if the dose is high enough (i.e., 1000 to 2000 μg daily) to provide absorption through a mechanism that does not require intrinsic factor, such as passive diffusion or mass action.
2,3
These forms of vitamin B
12
may be comparable or even superior to intramuscular injection for the treatment of cobalamin deficiency in patients with impaired . . .
Ataxia-telangiectasia (A-T) is an autosomal recessive chromosome breakage disorder caused by mutations in the ATM gene. Typically, it presents in early childhood with progressive cerebellar ...dysfunction along with immunodeficiency and oculocutaneous telangiectasia. An increased risk of malignancy is also associated with the syndrome and, rarely, may be the presenting feature in small children. We describe a 17-year-old boy with slurred speech, mild motor delays and learning disability diagnosed with atypical A-T in the setting of T-cell acute lymphoblastic leukemia. Suspicion for A-T was raised after review of a peripheral blood karyotype demonstrating rearrangements involving chromosomes 7 and/or 14. The diagnosis was confirmed after molecular testing identified a novel homozygous missense variant in ATM (c.5585T>A; p.Leu1862His) that resulted in protein instability and abolished serine/threonine protein kinase activity. To our knowledge, this is the first report of concurrent A-T and lymphoid malignancy diagnoses in an older child or adult with only mild neurological disease. Our experience suggests that screening for the disorder should be considered in any individual with lymphoid malignancy and neurological findings, especially as radiation and certain chemotherapy protocols are contraindicated in A-T.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Background: Autism spectrum disorder (ASD) is associated with high rates of psychiatric disturbance to include attention‐deficit/hyperactivity disorder (ADHD), tic disorder, and anxiety disorders. ...The aim of the present study was to examine the association between a variable number tandem repeat (VNTR) functional polymorphism located in the 3’‐untranslated region of the dopamine transporter gene (DAT1) and the severity of these symptoms as well as the association between the DAT1 DdeI polymorphism and severity of tics.
Methods: Parents (n = 62) and teachers (n = 57) completed a DSM‐IV‐referenced rating scale for 67 children with ASD.
Results: According to parent ratings, children with the 10‐10 repeat allele (versus a combined group of all other genotypes) exhibited less severe symptoms of hyperactivity and impulsivity as well as less severe language deficits. Teacher ratings indicated that social anxiety and tic symptoms were more severe for children with the 10‐10 genotype versus all others. Exploratory analyses provided preliminary support for the notion that heterozygosity (9–10 repeat genotype) may be a risk/protective factor. There were no associations of tic severity with the DAT1 DdeI polymorphism.
Conclusion: Collectively, these results suggest that the extraordinary variability in ASD clinical phenotypes may be explained in part by the same genes that are implicated in a host of other psychiatric disorders in non‐ASD populations. Nevertheless, replication with independent samples is necessary to confirm this preliminary finding.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
Background: Moderate hyperhomocysteinemia is an attractive target for intervention because it is present in 5–7% of the population and can be reversed by diet. This approach presupposes that ...hyperhomocysteinemia is directly involved in the disease process. Epidemiologic studies have indicated that moderately elevated homocysteine may contribute to thoracic aortic aneurysm (TAA) dilatation and dissection in humans. In vitro, elevated homocysteine disrupts the structure and function of extracellular matrix components, suggesting that moderate hyperhomocysteinemia may contribute to the development and/or progression of TAA. Objective: We investigated moderately elevated homocysteine in the development and progression of TAA in a mouse model of Marfan syndrome (MFS) and in isogenic wild-type mice. The MFS mouse is a well-described model of a systemic connective tissue disorder characterized by thoracic aortic dilatation, dissection, and rupture. We used this model as a sensitized indicator system to examine the impact of homocysteine on the progression of TAA. Methods: Murine fibrillin 1 gene (Fbn1)C1039G/+ MFS and C57BL/6J wild-type mice were fed a cobalamin-restricted diet to induce moderate hyperhomocysteinemia from weaning until the age of 32 wk. Homocysteine and methylmalonic acid were measured and aortic root diameter assessed with the use of echocardiography in mice aged 3, 7, 15, and 32 wk. Results: Cobalamin-restricted mice exhibited significantly higher homocysteine (P < 0.0001) and methylmalonic acid (P < 0.0001) in the blood. For both strains, no significant difference in thoracic aortic diameter was observed in mice on the cobalamin-restricted diet compared with those on the control diet. Conclusions: Fbn1C1039G/+ mice are a well-characterized model of progressive aortic root dilation. Hyperhomocysteinemia in the physiologic range did not induce abnormal aortic growth in wild-type mice and did not accelerate or otherwise influence aortic root growth and pathologic progression in mice with an underlying predisposition for aortic dilatation.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Abstract
Purpose
To characterize a novel neurodevelopmental syndrome due to loss-of-function (LoF) variants in Ankyrin 2 (ANK2), and to explore the effects on neuronal network dynamics and ...homeostatic plasticity in human-induced pluripotent stem cell-derived neurons.
Methods
We collected clinical and molecular data of 12 individuals with heterozygous de novo LoF variants in ANK2. We generated a heterozygous LoF allele of ANK2 using CRISPR/Cas9 in human-induced pluripotent stem cells (hiPSCs). HiPSCs were differentiated into excitatory neurons, and we measured their spontaneous electrophysiological responses using micro-electrode arrays (MEAs). We also characterized their somatodendritic morphology and axon initial segment (AIS) structure and plasticity.
Results
We found a broad neurodevelopmental disorder (NDD), comprising intellectual disability, autism spectrum disorders and early onset epilepsy. Using MEAs, we found that hiPSC-derived neurons with heterozygous LoF of ANK2 show a hyperactive and desynchronized neuronal network. ANK2-deficient neurons also showed increased somatodendritic structures and altered AIS structure of which its plasticity is impaired upon activity-dependent modulation.
Conclusions
Phenotypic characterization of patients with de novo ANK2 LoF variants defines a novel NDD with early onset epilepsy. Our functional in vitro data of ANK2-deficient human neurons show a specific neuronal phenotype in which reduced ANKB expression leads to hyperactive and desynchronized neuronal network activity, increased somatodendritic complexity and AIS structure and impaired activity-dependent plasticity of the AIS.
•Parents reported that educational videos were helpful in understanding genetics.•Satisfaction with genetic counseling was equivalent for standard care and videos.•Genetic counselors did not report ...significant differences between the two groups.•Creating effective and efficient educational tools is challenging.•Standardized measures of educational tools need to be developed and validated.
Growing use of clinical exome sequencing (CES) has led to an increased burden of genomic education. Self-guided educational tools can minimize the educational burden for genetic counselors (GCs). The effectiveness of these tools must be evaluated.
Parents of patients offered CES were randomized to watch educational videos before their visit or to receive routine care. Parents and GCs were surveyed about their experiences following the sessions. The responses of the video (n = 102) and no-video (n = 105) groups were compared.
GCs reported no significant differences between parents in the video and no-video groups on genetics knowledge or CES knowledge. In contrast, parents’ scores on genetics knowledge questions were lower in the video than no-video group (p = 0.007). Most parents reported the videos were informative, and the groups did not differ in satisfaction with GCs or decisions to have CES.
GCs and parents perceived the videos to be beneficial. However, lower scores on genetics knowledge questions highlight the need for careful development of educational tools.
Educational tools should be developed and assessed for effectiveness with the input of all stakeholders before widespread implementation. Better measures of the effectiveness of these educational tools are needed.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The aim of the study is to examine rs4680 (
COMT
) and rs6265 (
BDNF
) as genetic markers of anxiety, ADHD, and tics. Parents and teachers completed a DSM-IV-referenced rating scale for a total ...sample of 67 children with autism spectrum disorder (ASD). Both
COMT
(
p
= 0.06) and
BDNF
(
p
= 0.07) genotypes were marginally significant for teacher ratings of social phobia (η
p
2
= 0.06). Analyses also indicated associations of
BDNF
genotype with parent-rated ADHD (
p
= 0.01, η
p
2
= 0.10) and teacher-rated tics (
p
= 0.04; η
p
2
= 0.07). There was also evidence of a possible interaction (
p
= 0.02, η
p
2
= 0.09) of
BDNF
genotype with
DAT1
3′ VNTR with tic severity.
BDNF
and
COMT
may be biomarkers for phenotypic variation in ASD, but these preliminary findings remain tentative pending replication with larger, independent samples.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
Gigantism, Acromegaly, and GPR101 Mutations Kamenický, Peter; Bouligand, Jérôme; Chanson, Philippe ...
New England journal of medicine/The New England journal of medicine,
03/2015, Volume:
372, Issue:
13
Journal Article, Web Resource
Peer reviewed
Open access
To the Editor:
Trivellin et al. (Dec. 18 issue)
1
report a recurrent activating
GPR101
mutation (p.E308D) in 11 of 248 tumor DNA samples from patients with isolated acromegaly. Of these patients, 3 ...carried a germline
GPR101
mutation. Two of the 3 patients are being treated at our institution and were identified among 38 patients from our cohort. This might suggest a higher prevalence of germline
GPR101
mutation among French patients with sporadic acromegaly.
We therefore screened our entire cohort of 263 patients with gigantism or acromegaly for germline mutations in
GPR101,
which encodes a G-protein–coupled receptor, and in
AIP,
which . . .
Investigated association of single nucleotide polymorphism (SNP) rs301430 in glutamate transporter gene (
SLC1A1
) with severity of repetitive behaviors (obsessive–compulsive behaviors, tics) and ...anxiety in children with autism spectrum disorder (ASD). Mothers and/or teachers completed a validated DSM-IV-referenced rating scale for 67 children with autism spectrum disorder. Although analyses were not significant for repetitive behaviors, youths homozygous for the high expressing C allele had more severe anxiety than carriers of the T allele. Allelic variation in
SLC1A1
may be a biomarker for or modifier of anxiety symptom severity in children with ASD, but study findings are best conceptualized as tentative pending replication with larger independent samples.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, ODKLJ, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, VSZLJ, ZAGLJ
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