Rett syndrome (MECP2) and succinic semialdehyde dehydrogenase (ALDH5A1) deficiency in a developmentally delayed female

Madalyn Brown, Paula Ashcraft, Erland Arning, Teodoro Bottiglieri, William McClintock, Frank Giancola, David Lieberman, Natalie S. Hauser, Rebecca Miller, Jean-Baptiste Roullet, Phillip Pearl, K. Michael Gibson

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

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.

Original languageEnglish (US)
Article numbere629
JournalMolecular Genetics and Genomic Medicine
Volume7
Issue number5
DOIs
StatePublished - May 1 2019
Externally publishedYes

Fingerprint

Succinate-Semialdehyde Dehydrogenase
Rett Syndrome
Aldehyde Dehydrogenase
Phenotype
gamma-Aminobutyric Acid
Hydroxybutyrates
Exome
Aminobutyrates
Mutation
Muscle Hypotonia
GABA Receptors
Nonsense Codon
Autistic Disorder
Tandem Mass Spectrometry
Gait
Neurotransmitter Agents
Hand
Mothers
succinic semialdehyde dehydrogenase deficiency

Keywords

  • autism spectrum disorder
  • GABA (γ-aminobutyric acid)
  • GHB (γ-hydroxybutyric acid)
  • Rett syndrome
  • succinic semialdehyde dehydrogenase
  • succinic semialdehyde dehydrogenase deficiency

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Brown, M., Ashcraft, P., Arning, E., Bottiglieri, T., McClintock, W., Giancola, F., ... Gibson, K. M. (2019). Rett syndrome (MECP2) and succinic semialdehyde dehydrogenase (ALDH5A1) deficiency in a developmentally delayed female. Molecular Genetics and Genomic Medicine, 7(5), [e629]. https://doi.org/10.1002/mgg3.629

Rett syndrome (MECP2) and succinic semialdehyde dehydrogenase (ALDH5A1) deficiency in a developmentally delayed female. / Brown, Madalyn; Ashcraft, Paula; Arning, Erland; Bottiglieri, Teodoro; McClintock, William; Giancola, Frank; Lieberman, David; Hauser, Natalie S.; Miller, Rebecca; Roullet, Jean-Baptiste; Pearl, Phillip; Gibson, K. Michael.

In: Molecular Genetics and Genomic Medicine, Vol. 7, No. 5, e629, 01.05.2019.

Research output: Contribution to journalArticle

Brown, M, Ashcraft, P, Arning, E, Bottiglieri, T, McClintock, W, Giancola, F, Lieberman, D, Hauser, NS, Miller, R, Roullet, J-B, Pearl, P & Gibson, KM 2019, 'Rett syndrome (MECP2) and succinic semialdehyde dehydrogenase (ALDH5A1) deficiency in a developmentally delayed female', Molecular Genetics and Genomic Medicine, vol. 7, no. 5, e629. https://doi.org/10.1002/mgg3.629
Brown, Madalyn ; Ashcraft, Paula ; Arning, Erland ; Bottiglieri, Teodoro ; McClintock, William ; Giancola, Frank ; Lieberman, David ; Hauser, Natalie S. ; Miller, Rebecca ; Roullet, Jean-Baptiste ; Pearl, Phillip ; Gibson, K. Michael. / Rett syndrome (MECP2) and succinic semialdehyde dehydrogenase (ALDH5A1) deficiency in a developmentally delayed female. In: Molecular Genetics and Genomic Medicine. 2019 ; Vol. 7, No. 5.
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abstract = "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.",
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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

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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.

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