TY - JOUR
T1 - Rett syndrome (MECP2) and succinic semialdehyde dehydrogenase (ALDH5A1) deficiency in a developmentally delayed female
AU - Brown, Madalyn
AU - Ashcraft, Paula
AU - Arning, Erland
AU - Bottiglieri, Teodoro
AU - McClintock, William
AU - Giancola, Frank
AU - Lieberman, David
AU - Hauser, Natalie S.
AU - Miller, Rebecca
AU - Roullet, Jean Baptiste
AU - Pearl, Phillip
AU - Gibson, K. Michael
N1 - Publisher Copyright:
© 2019 Washington State University College of Pharmacy. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
PY - 2019/5
Y1 - 2019/5
N2 - Background: We present a patient with Rett syndrome (RTT; MECP2) and autosomal-recessive succinic semialdehyde dehydrogenase deficiency (SSADHD; ALDH5A1 (aldehyde dehydrogenase 5a1 = SSADH), in whom the current phenotype exhibits features of SSADHD (hypotonia, global developmental delay) and RTT (hand stereotypies, gait anomalies). Methods: γ-Hydroxybutyric acid (GHB) was quantified by UPLC-tandem mass spectrometry, while mutation analysis followed standard methodology of whole-exome sequencing. Results: The biochemical hallmark of SSADHD, GHB was increased in the proband's dried bloodspot (DBS; 673 µM; previous SSADHD DBSs (n = 7), range 124–4851 µM); control range (n = 2,831), 0–78 µM. The proband was compound heterozygous for pathogenic ALDH5A1 mutations (p.(Asn418IlefsTer39); maternal; p.(Gly409Asp); paternal) and a de novo RTT nonsense mutation in MECP2 (p.Arg255*). Conclusion: The major inhibitory neurotransmitter, γ-aminobutyric acid (GABA), is increased in SSADHD but normal in RTT, although there are likely regional changes in GABA receptor distribution. GABAergic anomalies occur in both disorders, each featuring an autism spectrum phenotype. What effect the SSADHD biochemical anomalies (elevated GABA, GHB) might play in the neurodevelopmental/epileptic phenotype of our patient is currently unknown.
AB - Background: We present a patient with Rett syndrome (RTT; MECP2) and autosomal-recessive succinic semialdehyde dehydrogenase deficiency (SSADHD; ALDH5A1 (aldehyde dehydrogenase 5a1 = SSADH), in whom the current phenotype exhibits features of SSADHD (hypotonia, global developmental delay) and RTT (hand stereotypies, gait anomalies). Methods: γ-Hydroxybutyric acid (GHB) was quantified by UPLC-tandem mass spectrometry, while mutation analysis followed standard methodology of whole-exome sequencing. Results: The biochemical hallmark of SSADHD, GHB was increased in the proband's dried bloodspot (DBS; 673 µM; previous SSADHD DBSs (n = 7), range 124–4851 µM); control range (n = 2,831), 0–78 µM. The proband was compound heterozygous for pathogenic ALDH5A1 mutations (p.(Asn418IlefsTer39); maternal; p.(Gly409Asp); paternal) and a de novo RTT nonsense mutation in MECP2 (p.Arg255*). Conclusion: The major inhibitory neurotransmitter, γ-aminobutyric acid (GABA), is increased in SSADHD but normal in RTT, although there are likely regional changes in GABA receptor distribution. GABAergic anomalies occur in both disorders, each featuring an autism spectrum phenotype. What effect the SSADHD biochemical anomalies (elevated GABA, GHB) might play in the neurodevelopmental/epileptic phenotype of our patient is currently unknown.
KW - GABA (γ-aminobutyric acid)
KW - GHB (γ-hydroxybutyric acid)
KW - Rett syndrome
KW - autism spectrum disorder
KW - succinic semialdehyde dehydrogenase
KW - succinic semialdehyde dehydrogenase deficiency
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U2 - 10.1002/mgg3.629
DO - 10.1002/mgg3.629
M3 - Article
C2 - 30829465
AN - SCOPUS:85065426436
SN - 2324-9269
VL - 7
JO - Molecular Genetics and Genomic Medicine
JF - Molecular Genetics and Genomic Medicine
IS - 5
M1 - e629
ER -