DDC Clinic for Special Needs Children

Middlefield, OH, United States

DDC Clinic for Special Needs Children

Middlefield, OH, United States
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Henrickson M.,Cincinnati Childrens Hospital Medical Center | Wang H.,DDC Clinic for Special Needs Children
Clinical Rheumatology | Year: 2017

An auto-inflammatory syndrome consequent to SAMHD1 mutations involves cerebral vasculopathy characterized by multifocal stenosis and aneurysms within large arteries, moyamoya, chronic ischemia, and early-onset strokes (SAMS). While this condition involves the innate immune system, additional clinical features mimic systemic lupus erythematosus. Mutations in this gene can also cause a subset of the rare genetic condition Aicardi-Goutières syndrome. To date, no established therapy successfully prevents disease progression. We report a corticosteroid-dependent SAMS patient, a 19-year-old male of Old Order Amish ancestry, with diffuse cerebral arteriopathy identified through contrast brain magnetic resonance arteriography (MRA) and MRI. He received subcutaneous adalimumab every 2 weeks for 9 months with minimal response. Then, he started intravenous tocilizumab (6 mg/kg/dose) every 4 weeks. He sustained steadily normalizing cerebral vasculopathy and lab abnormalities resolved, allowing prednisone reduction. We conclude that the cerebral vasculopathy of the homozygous SAMHD1 mutation-mediated auto-inflammatory disease SAMS responded favorably to tocilizumab infusion therapy. © 2017 The Author(s)


Nagy R.,Ohio State University | Wang H.,DDC Clinic for Special Needs Children | Albrecht B.,University of Duisburg - Essen | Wieczorek D.,University of Duisburg - Essen | And 7 more authors.
Clinical Genetics | Year: 2012

Microcephalic osteodysplastic primordial dwarfism type I (MOPD I) is a rare autosomal recessive developmental disorder characterized by extreme intrauterine growth retardation, severe microcephaly, central nervous system abnormalities, dysmorphic facial features, skin abnormalities, skeletal changes, limb deformations, and early death. Recently, mutations in the RNU4ATAC gene, which encodes U4atac, a small nuclear RNA that is a crucial component of the minor spliceosome, were found to cause MOPD I. MOPD I is the first disease known to be associated with a defect in small nuclear RNAs. We describe here the clinical and molecular data for 17 cases of MOPD I, including 15 previously unreported cases, all carrying biallelic mutations in the RNU4ATAC gene. © 2011 John Wiley & Sons A/S.


Xin B.,DDC Clinic for Special Needs Children | Puffenberger E.G.,Clinic for Special Children | Puffenberger E.G.,Franklin And Marshall College | Turben S.,DDC Clinic for Special Needs Children | And 5 more authors.
Proceedings of the National Academy of Sciences of the United States of America | Year: 2010

We identified an autosomal recessive condition in 11 individuals in the Old Order Amish of northeastern Ohio. The syndrome was characterized by distinctive craniofacial dysmorphism, skeletal anomalies, and mental retardation. The typical craniofacial dysmorphism included brachycephaly, highly arched bushy eyebrows, synophrys, long eyelashes, low-set ears, microdontism of primary teeth, and generalized gingival hyperplasia, whereas Sprengel deformity of scapula, fusion of spine, rib abnormities, pectus excavatum, and pes planus represented skeletal anomalies. The genome-wide homozygosity mapping using six affected individuals localized the disease gene to a 3.3-Mb region on chromosome 1q23.3-q24.1. Candidate gene sequencing identified a homozygous frameshift mutation, c.139-140delAG, in the transmembrane and coiled-coil domains 1 (TMCO1) gene, as the pathogenic change in all affected members of the extended pedigree. This mutation is predicted to result in a severely truncated protein (p.Ser47Ter) of only one-fourth the original length. The TMCO1 gene product is a member of DUF841 superfamily of several eukaryotic proteins with unknown function. The gene has highly conserved amino acid sequence and is universally expressed in all human tissues examined. The high degree of conservation and the ubiquitous expression pattern in human adult and fetal tissues suggest a critical role for TMCO1. This report shows a TMCO1 sequence variant being associated with a genetic disorder in human. We propose "TMCO1 defect syndrome" as the name of this condition.


Wang H.,DDC Clinic for Special Needs Children | Wang H.,Case Western Reserve University | Wang H.,Rainbow Babies and Childrens Hospital | Wang H.,Cleveland Clinic | And 4 more authors.
American Journal of Medical Genetics, Part A | Year: 2013

Ganglioside GM3 synthase deficiency is a rare autosomal recessive metabolic disorder characterized by infantile onset of severe irritability and epilepsy, failure to thrive, developmental stagnation, and cortical blindness. Because of the lack of easily recognizable dysmorphism and specific neurologic manifestations, identification of patients with this condition is extremely challenging. Here we report on previously undescribed pigmentary abnormalities in 20 of 38 patients with GM3 synthase deficiency. All 20 of the patients showed freckle-like hyperpigmented macules, ranging in size from 2 to 5mm in diameter and usually found bilaterally on the extremities, especially the dorsal aspects of the hands and feet. Seven of these patients also had depigmented macules and patches, especially on the face and extremities. These cutaneous changes were asymptomatic, and were not associated with the severity or particular phenotype of the neurologic disease. They became visible only after the first years of life with an increased incidence with advancing age. These distinct pigmentary features are not identified in 54 normal siblings, and may provide a useful clue in identifying patients with ganglioside metabolic disorders. © 2013 Wiley Periodicals, Inc.


Xin B.,DDC Clinic for Special Needs Children | Wang H.,DDC Clinic for Special Needs Children | Wang H.,Rainbow Babies and Childrens Hospital | Wang H.,Cleveland Clinic
Molecular Syndromology | Year: 2012

Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by progressive multisystem degeneration and segmental premature aging. Mutations in the DNA repair gene ERCC6 are responsible for the majority of CS cases reported. In this study, we identified 4 patients presenting with CS from 2 Old Order Amish families. Sequence analysis of the ERCC6 gene revealed 2 novel mutations associated with the disorder in these patients. The patients from family 1 were homozygous for a splice-site mutation, c.2709 + 1G>T, in intron 14 of ERCC6, whereas the patients from family 2 were compound heterozygous for c.2709 + 1G>T and a short deletion in exon 5 (c.1293-1320del). Our findings provide evidence of allelic heterogeneity in Old Order Amish, which is extremely uncommon for a rare condition in an isolated founder population. Copyright © 2012 S. Karger AG, Basel.


Wang H.,DDC Clinic for Special Needs Children | Wang H.,Rainbow Babies and Childrens Hospital | Wang H.,Cleveland Clinic | Xin B.,DDC Clinic for Special Needs Children
Progress in Pediatric Cardiology | Year: 2011

Hypertrophic cardiomyopathy is one of the most common inherited cardiac disorders, with a prevalence of 1:500 in the general population. We have recently reported a severe neonatal hypertrophic cardiomyopathy caused by a novel homozygous splice site c.3330 + 2 T > G mutation in the MYBPC3 gene in an Amish community. The affected children typically presented with signs and symptoms of congestive heart failure during the first three weeks of life, and most of them died before one year of age unless they received a heart transplant. Since the condition is inherited in an autosomal dominant pattern with incomplete penetrance, further studies to understand the clinical course in the heterozygous carrier of c.3330 + 2 T > G mutation were performed when we provided the service of carrier testing in the community. The preliminary results indicated a relatively low incidence of the phenotypic expression of hypertrophic cardiomyopathy, although the disease was identified in a few heterozygous carriers before they reached to their adolescence. Significant variation of the phenotypic expression suggests the complexity of the disease development. The Amish community is often composed of genetically and geographically isolated, large, multigenerational families with similar environmental influences, and potentially harbors a reduced number of risk factors compared to a more heterogeneous population. Therefore, our further study will not only benefit the Amish population but also will help us to understand the hypertrophic cardiomyopathy as a whole, for the disease development, diagnosis, treatment, and prognosis. Partnering with the community to establish solid, trustful relationships with the affected families and to provide much needed services to them has been the key to success in the past and will remain essential for our future study. © 2011 Elsevier Ireland Ltd.


Xin B.,DDC Clinic for Special Needs Children | Wang H.,DDC Clinic for Special Needs Children | Wang H.,Rainbow Babies and Childrens Hospital | Wang H.,Cleveland Clinic
Clinical Genetics | Year: 2011

Glucose-galactose malabsorption (GGM) is an autosomal recessive disease with life-threatening newborn diarrhea caused by mutations in the Na+/glucose cotransporter gene SLC5A1. Because of its rarity, the clinical course of the disease has not been well studied. Here, we report 33 patients with GGM from a large Old Order Amish pedigree and the associated mutations in SLC5A1 gene. Clinically, all affected individuals presented with classic watery diarrhea and dehydration. The increased bowel sounds, distended abdomen, vigorous nursing regardless of their illness, and irritability and apathy were also noted as part of the initial presentation. Patients underwent a dramatic turnaround with an immediate cease of the diarrhea and a quick rehydration if they were correctly diagnosed and adequately managed, followed by a normal growth and development pattern afterwards; whereas a prolonged clinical course would follow if the disease was not recognized. Sequence analysis of the 15 protein-coding exons and the corresponding exon-intron boundaries of SLC5A1 gene revealed four homozygous missense mutations, c.152A>G (p.N51S), c.1231G>A (p.A411T), c.1673G>A (p.R558H), and c.1845C>G (p.H615Q), that co-segregate with the GGM phenotype in all of the affected individuals. These findings suggest that founder effect of the SLC5A1 mutations associated with the disease in Amish and a population specific genetic testing is in need to pursue an early diagnosis which is critical for a favorable outcome. © 2010 John Wiley & Sons A/S.


Li W.,Capital Medical University | Li W.,Beijing Neurosurgical Institute | Hu B.,Cleveland Clinic | Li G.-L.,Beijing Neurosurgical Institute | And 11 more authors.
CNS Neuroscience and Therapeutics | Year: 2012

Aims: With developments of etiology of cerebral small vessel disease (CSVD) and genome-wide association study (GWAS) of stroke, the genetic studies of CSVD are focused on genes related to blood-brain barrier (BBB) and aging. The project aims to investigate the association between CSVD and susceptibility loci and candidate genes. Methods: All study subjects admitted Beijing Tiantan Hospital from June 2009 to September 2010 including 197 cerebral small vessel disease patients(S), 198 large artery atherosclerosis control individuals (vascular stenotic rate ≥50% diameter reduction) (L), 200 hypertensive intracerebral hemorrhage control individuals (H) and 197 stroke-free control individuals (C). 15 SNPs in 4 genes (MYLK, AQP4, NINJ2, and INK4/ARF) were genotyped using Multiplex Snapshot assay. Each SNP was first examined between the groups S and C in different genetic models (codominant, dominant, recessive, overdominant, and log-additive). Permutation correction was used to adjust for multiple testing. The significant SNP loci were further analyzed in comparing S with L and H, respectively. Subgroup analysis was also performed for each risk-factor category. Results: Among the 15 SNPs, rs2222823 and rs2811712 were found to be significantly associated with CSVD after multiple-testing adjustment. The heterozygote (A/T) of rs2222823 of MYLK has an odds ratio of 0.52 (95% CI =[0.35, 0.79], P= 0.002, adjusted P= 0.031) when compared with homozygotes. The heterozygote (C/T) of rs2811712 of INK4/ARF has an odds ratio of 1.75 (95% CI =[1.13-2.71], P= 0.004, adjusted P= 0.050). The SNP rs2222823 was significant (P= 0.035) in comparing S with H. In comparing S versus L, it is significant for the subgroups of patients without diabetes (P= 0.012) and drinking (P= 0.018). rs2811712 was significant in comparing S with L for the subgroups of patients with hyperlipidemia (P= 0.029) and drinking (P= 0.04). Conclusion: The heterozygotes (T/A) at the rs2222823 SNP locus of MYLK gene decreases the risk of having cerebral small vessel disease, while the heterozygotes (C/T) at the rs2811712 SNP locus of INK4/ARF gene increases the risk, suggesting that the MYLK and INK4/ARF are the associated genes of cerebral small vessel disease in Han Chinese population. © 2012 Blackwell Publishing Ltd.


PubMed | DDC Clinic for Special Needs Children
Type: Journal Article | Journal: American journal of medical genetics. Part A | Year: 2013

Ganglioside GM3 synthase deficiency is a rare autosomal recessive metabolic disorder characterized by infantile onset of severe irritability and epilepsy, failure to thrive, developmental stagnation, and cortical blindness. Because of the lack of easily recognizable dysmorphism and specific neurologic manifestations, identification of patients with this condition is extremely challenging. Here we report on previously undescribed pigmentary abnormalities in 20 of 38 patients with GM3 synthase deficiency. All 20 of the patients showed freckle-like hyperpigmented macules, ranging in size from 2 to 5 mm in diameter and usually found bilaterally on the extremities, especially the dorsal aspects of the hands and feet. Seven of these patients also had depigmented macules and patches, especially on the face and extremities. These cutaneous changes were asymptomatic, and were not associated with the severity or particular phenotype of the neurologic disease. They became visible only after the first years of life with an increased incidence with advancing age. These distinct pigmentary features are not identified in 54 normal siblings, and may provide a useful clue in identifying patients with ganglioside metabolic disorders.


PubMed | DDC Clinic for Special Needs Children
Type: Journal Article | Journal: Molecular syndromology | Year: 2013

Cockayne syndrome (CS) is a rare autosomal recessive disorder characterized by progressive multisystem degeneration and segmental premature aging. Mutations in the DNA repair gene ERCC6 are responsible for the majority of CS cases reported. In this study, we identified 4 patients presenting with CS from 2 Old Order Amish families. Sequence analysis of the ERCC6 gene revealed 2 novel mutations associated with the disorder in these patients. The patients from family 1 were homozygous for a splice-site mutation, c.2709 + 1G>T, in intron 14 of ERCC6, whereas the patients from family 2 were compound heterozygous for c.2709 + 1G>T and a short deletion in exon 5 (c.1293_1320del). Our findings provide evidence of allelic heterogeneity in Old Order Amish, which is extremely uncommon for a rare condition in an isolated founder population.

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