Abstract
Background: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder that affects the degradation of gamma-aminobutyric acid and leads to the accumulation of gamma-hydroxybutyric acid (GHB) in body fluids. Diagnosis of SSADH deficiency is challenging, since the neurological symptoms are non-specific. Case: The patient is a nine-year-old Japanese boy who presented with developmental delay, autism, epilepsy, and episodic gait disturbance. Brain magnetic resonance imaging showed hyperintense lesions in the bilateral thalami, globus pallidi, substantia nigra, and dentate nuclei. Urine metabolome analysis revealed elevated GHB, which led to a biochemical diagnosis of SSADH deficiency. Genetic analysis of the ALDH5A1 gene revealed a novel missense mutation c.1586G>A inherited from his father. It also demonstrated three single nucleotide polymorphisms (SNPs) (c.106G>C, c.538C>T, and c.545C>T), all of which were inherited from his mother and are known to reduce SSADH enzyme activity. There were no duplications or deletions in other exons in the patient or his parents. No variants in the upstream, intronic, or downstream regions of the ALDH5A1 gene were found in the patient. Enzymatic assay revealed a marked reduction of SSADH enzyme activity (≈2% of the lower limit of the normal range). Conclusion: Although other mechanisms cannot be fully excluded, the clinical manifestation of SSADH deficiency in this patient may be attributed to the combined effect of the mutation and the three enzyme activity-reducing SNPs. Urine metabolome analysis effectively detected his elevated GHB and is thus considered to be a good screening method for this underdiagnosed and potentially manageable metabolic disorder.
| Original language | English |
|---|---|
| Journal | Brain and Development |
| DOIs | |
| Publication status | Accepted/In press - 2016 |
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Keywords
- ALDH5A1 gene
- Gamma-aminobutyric acid
- Gamma-hydroxybutyric acid
- Metabolome analysis
ASJC Scopus subject areas
- Clinical Neurology
- Developmental Neuroscience
- Pediatrics, Perinatology, and Child Health
Cite this
SSADH deficiency possibly associated with enzyme activity-reducing SNPs. / Akiyama, Tomoyuki; Osaka, Hitoshi; Shimbo, Hiroko; Kuhara, Tomiko; Shibata, Takashi; Kobayashi, Katsuhiro; Kurosawa, Kenji; Yoshinaga, Harumi.
In: Brain and Development, 2016.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - SSADH deficiency possibly associated with enzyme activity-reducing SNPs
AU - Akiyama, Tomoyuki
AU - Osaka, Hitoshi
AU - Shimbo, Hiroko
AU - Kuhara, Tomiko
AU - Shibata, Takashi
AU - Kobayashi, Katsuhiro
AU - Kurosawa, Kenji
AU - Yoshinaga, Harumi
PY - 2016
Y1 - 2016
N2 - Background: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder that affects the degradation of gamma-aminobutyric acid and leads to the accumulation of gamma-hydroxybutyric acid (GHB) in body fluids. Diagnosis of SSADH deficiency is challenging, since the neurological symptoms are non-specific. Case: The patient is a nine-year-old Japanese boy who presented with developmental delay, autism, epilepsy, and episodic gait disturbance. Brain magnetic resonance imaging showed hyperintense lesions in the bilateral thalami, globus pallidi, substantia nigra, and dentate nuclei. Urine metabolome analysis revealed elevated GHB, which led to a biochemical diagnosis of SSADH deficiency. Genetic analysis of the ALDH5A1 gene revealed a novel missense mutation c.1586G>A inherited from his father. It also demonstrated three single nucleotide polymorphisms (SNPs) (c.106G>C, c.538C>T, and c.545C>T), all of which were inherited from his mother and are known to reduce SSADH enzyme activity. There were no duplications or deletions in other exons in the patient or his parents. No variants in the upstream, intronic, or downstream regions of the ALDH5A1 gene were found in the patient. Enzymatic assay revealed a marked reduction of SSADH enzyme activity (≈2% of the lower limit of the normal range). Conclusion: Although other mechanisms cannot be fully excluded, the clinical manifestation of SSADH deficiency in this patient may be attributed to the combined effect of the mutation and the three enzyme activity-reducing SNPs. Urine metabolome analysis effectively detected his elevated GHB and is thus considered to be a good screening method for this underdiagnosed and potentially manageable metabolic disorder.
AB - Background: Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder that affects the degradation of gamma-aminobutyric acid and leads to the accumulation of gamma-hydroxybutyric acid (GHB) in body fluids. Diagnosis of SSADH deficiency is challenging, since the neurological symptoms are non-specific. Case: The patient is a nine-year-old Japanese boy who presented with developmental delay, autism, epilepsy, and episodic gait disturbance. Brain magnetic resonance imaging showed hyperintense lesions in the bilateral thalami, globus pallidi, substantia nigra, and dentate nuclei. Urine metabolome analysis revealed elevated GHB, which led to a biochemical diagnosis of SSADH deficiency. Genetic analysis of the ALDH5A1 gene revealed a novel missense mutation c.1586G>A inherited from his father. It also demonstrated three single nucleotide polymorphisms (SNPs) (c.106G>C, c.538C>T, and c.545C>T), all of which were inherited from his mother and are known to reduce SSADH enzyme activity. There were no duplications or deletions in other exons in the patient or his parents. No variants in the upstream, intronic, or downstream regions of the ALDH5A1 gene were found in the patient. Enzymatic assay revealed a marked reduction of SSADH enzyme activity (≈2% of the lower limit of the normal range). Conclusion: Although other mechanisms cannot be fully excluded, the clinical manifestation of SSADH deficiency in this patient may be attributed to the combined effect of the mutation and the three enzyme activity-reducing SNPs. Urine metabolome analysis effectively detected his elevated GHB and is thus considered to be a good screening method for this underdiagnosed and potentially manageable metabolic disorder.
KW - ALDH5A1 gene
KW - Gamma-aminobutyric acid
KW - Gamma-hydroxybutyric acid
KW - Metabolome analysis
UR - http://www.scopus.com/inward/record.url?scp=84962027504&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84962027504&partnerID=8YFLogxK
U2 - 10.1016/j.braindev.2016.03.008
DO - 10.1016/j.braindev.2016.03.008
M3 - Article
JO - Brain and Development
JF - Brain and Development
SN - 0387-7604
ER -