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ABSTRACT: Pompe disease (acid-alpha-glucosidase deficiency) encompasses a clinical spectrum, ranging from severe infantile-onset disease with clinical symptoms appearing before 1 year of age with rapid progression to an early death, to late-onset disease with a much more variable age at onset and disease course. Sibling phenotype discordance has been reported for late-onset Pompe disease, but has not been studied in classical infantile disease. We reviewed the medical literature for affected sibships in which at least one sibling had clinical and pathology or biochemical findings consistent with infantile Pompe disease including symptoms beginning in infancy, early hypotonia, cardiomegaly documented by 6 months of age, and early death. The age at symptom onset, age at death, and clinical course were compared between probands and affected siblings. Our results showed that since 1931, publications document 13 families with 31 affected infants (11 probands; 20 affected siblings). The median age at symptom onset for all affected infants was 3 months (range 0-6 months) with significant correlation (R = 0.60, P = 0.04) between probands and affected siblings. The median age at death for all affected infants was 6 months (range 1.5-13 months); probands were slightly older at death than their siblings. The median length of disease course for all affected infants was 3 months (0-10 months) and was slightly longer for probands. Unlike late-onset Pompe disease, there appears to be minimal phenotypic and lifespan variation among siblings with infantile Pompe disease. This prognostic information is vital for families with affected infants and allows for appropriate genetic counseling.
American Journal of Medical Genetics Part A 12/2007; 143A(21):2493-501. · 2.39 Impact Factor
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Deborah A McDermott,
Michael C Bressan,
Jie He,
Joseph S Lee,
Salim Aftimos,
Martina Brueckner,
Fred Gilbert,
Gail E Graham,
Mark C Hannibal,
Jeffrey W Innis,
Mary Ella Pierpont,
Annick Raas-Rothschild,
Alan L Shanske, Wendy E Smith,
Robert H Spencer,
Martin G St John-Sutton,
Lionel van Maldergem,
Darrel J Waggoner,
Matthew Weber,
Craig T Basson
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ABSTRACT: Holt-Oram syndrome (HOS) is an autosomal dominant heart-hand syndrome characterized by congenital heart disease (CHD) and upper limb deformity, and caused by mutations in the TBX5 gene. To date, the sensitivity of TBX5 genetic testing for HOS has been unclear. We now report mutational analyses of a nongenetically selected population of 54 unrelated individuals who were consecutively referred to our center with a clinical diagnosis of HOS. TBX5 mutational analyses were performed in all individuals, and clinical histories and findings were reviewed for each patient without reference to the genotypes. Twenty-six percent of the complete cohort was shown to have mutations of the TBX5 gene. However, among those subjects for whom clinical review demonstrated that their presentations met strict diagnostic criteria for HOS, TBX5 mutations were identified in 74%. No mutations were identified in those subjects who did not meet these criteria. Thus, these studies validate our clinical diagnostic criteria for HOS including an absolute requirement for preaxial radial ray upper limb malformation. Accordingly, TBX5 genotyping has high sensitivity and specificity for HOS if stringent diagnostic criteria are used in assigning the clinical diagnosis.
Pediatric Research 12/2005; 58(5):981-6. · 2.70 Impact Factor
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Regina E Ensenauer,
Adewale Adeyinka,
Heather C Flynn,
Virginia V Michels,
Noralane M Lindor,
D Brian Dawson,
Erik C Thorland,
Cindy Pham Lorentz,
Jennifer L Goldstein,
Marie T McDonald, Wendy E Smith,
Elba Simon-Fayard,
Alan A Alexander,
Anita S Kulharya,
Rhett P Ketterling,
Robin D Clark,
Syed M Jalal
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ABSTRACT: Chromosome 22, particularly band 22q11.2, is predisposed to rearrangements due to misalignments of low-copy repeats (LCRs). DiGeorge/velocardiofacial syndrome (DG/VCFS) is a common disorder resulting from microdeletion within the same band. Although both deletion and duplication are expected to occur in equal proportions as reciprocal events caused by LCR-mediated rearrangements, very few microduplications have been identified. We have identified 13 cases of microduplication 22q11.2, primarily by interphase fluorescence in situ hybridization (FISH). The size of the duplications, determined by FISH probes from bacterial artificial chromosomes and P(1) artificial chromosomes, range from 3-4 Mb to 6 Mb, and the exchange points seem to involve an LCR. Molecular analysis based on 15 short tandem repeats confirmed the size of the duplications and indicated that at least 1 of 15 loci has three alleles present. The patients' phenotypes ranged from mild to severe, sharing a tendency for velopharyngeal insufficiency with DG/VCFS but having other distinctive characteristics, as well. Although the present series of patients was ascertained because of some overlapping features with DG/VCF syndromes, the microduplication of 22q11.2 appears to be a new syndrome.
The American Journal of Human Genetics 12/2003; 73(5):1027-40. · 10.60 Impact Factor
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Dwight D Koeberl,
Sarah P Young,
Niels S Gregersen,
Jerry Vockley, Wendy E Smith,
Daniel Kelly Benjamin,
Yan An,
Susan D Weavil,
Shu H Chaing,
Deeksha Bali,
Marie T McDonald,
Priya S Kishnani,
Y-T Chen,
David S Millington
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ABSTRACT: Tandem mass spectrometry was adopted for newborn screening by North Carolina in April 1999. Since then, three infants with short-chain acyl-CoA dehydrogenase (SCAD) and one with isobutyryl-CoA dehydrogenase deficiency were detected on the basis of elevated butyrylcarnitine/isobutyrylcarnitine (C4-carnitine) concentrations in newborn blood spots analyzed by tandem mass spectrometry. For three SCAD-deficient infants, biochemical evaluation included a plasma acylcarnitine profile with markedly elevated C4-carnitine, urine organic acid analysis with markedly elevated ethylmalonic and 2-methylsuccinic acids, and markedly elevated [U-13C]butyrylcarnitine concentrations in medium from fibroblasts incubated with [U-13C]palmitic acid and excess l-carnitine, consistent with classic SCAD deficiency. Two of three infants diagnosed with classic SCAD deficiency remained asymptomatic; however, the third infant presented with seizures and a cerebral infarct at 10 wk of age. All three infants had putatively inactivating mutations in both alleles of the SCAD gene. The highly elevated plasma C4-carnitine levels in the three infants detected by newborn screening tandem mass spectrometry differentiated them from infants and children who were homozygous or compound heterozygous for one of two SCAD gene susceptibility variations; for the latter group the C4-carnitine levels were normal. Isobutyryl-CoA dehydrogenase deficiency in a fourth infant was confirmed after isolated elevation of C4-carnitine in the acylcarnitine profile.
Pediatric Research 09/2003; 54(2):219-23. · 2.70 Impact Factor
