|Year : 2020 | Volume
| Issue : 3 | Page : 297-300
Syndromic autism spectrum disorder: Let us not forget about succinic semialdehyde dehydrogenase deficiency. A case report with literature review
Annio Posar1, Paola Visconti2
1 IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Neuropsichiatria Infantile, Bologna, Italia; Dipartimento di Scienze Biomediche e Neuromotorie, Università di Bologna, Bologna, Italia
2 IRCCS Istituto delle Scienze Neurologiche di Bologna, UOC Neuropsichiatria Infantile, Bologna, Italia
|Date of Submission||21-Dec-2019|
|Date of Decision||19-Mar-2020|
|Date of Acceptance||28-Mar-2020|
|Date of Web Publication||06-Nov-2020|
Dr. Annio Posar
IRCCS Istituto delle Scienze Neurologiche di Bologna, Via Altura 3, Bologna.
Source of Support: None, Conflict of Interest: None
| Abstract|| |
We describe a girl with syndromic autism spectrum disorder (ASD), who at the end of the medical workup proved affected by a succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare autosomal-recessive disorder of degradation of the γ-aminobutyric acid (GABA), that is, the most important central nervous system inhibitory neurotransmitter. The diagnosis of SSADH deficiency was made using a next-generation sequencing (NGS) multigene panel for neurological disorders and was confirmed by urinary organic acid analysis. Compared to the classic description of SSADH deficiency, our patient presented a less severe picture. In fact, she had no epilepsy, and her neuromotor signs were soft, and over time they became less evident. This case report emphasizes the importance of considering in a patient with syndromic ASD, the possible diagnosis of SSADH deficiency, even when all its typical signs are not present. Nowadays, the use of NGS multigene panels could facilitate the etiological diagnosis in individuals with syndromic ASD.
Keywords: Epilepsy, intellectual disability, next-generation sequencing, succinic semialdehyde dehydrogenase deficiency, syndromic autism spectrum disorder
|How to cite this article:|
Posar A, Visconti P. Syndromic autism spectrum disorder: Let us not forget about succinic semialdehyde dehydrogenase deficiency. A case report with literature review. J Pediatr Neurosci 2020;15:297-300
|How to cite this URL:|
Posar A, Visconti P. Syndromic autism spectrum disorder: Let us not forget about succinic semialdehyde dehydrogenase deficiency. A case report with literature review. J Pediatr Neurosci [serial online] 2020 [cited 2022 Nov 29];15:297-300. Available from: https://www.pediatricneurosciences.com/text.asp?2020/15/3/297/300051
| Introduction|| |
Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by a persistent and pervasive impairment of social communication skills, associated with restricted and repetitive interests and activities. Syndromic ASD, representing nowadays only a minority of individuals with autism, by definition is associated with additional phenotypes and/or dysmorphisms, and in most of these cases, the etiology is known, including chromosomal abnormalities, copy number variations, and single-gene mutations. One of the single-gene conditions involved in syndromic ASD is the succinic semialdehyde dehydrogenase (SSADH) deficiency, a rare autosomal-recessive disorder of degradation of the γ-aminobutyric acid (GABA), which is the most important central nervous system inhibitory neurotransmitter. SSADH deficiency is due to the mutations of the Aldehyde Dehydrogenase 5 Family Member A1 (ALDH5A1) gene located on chromosome 6p22.3. In the GABA degradation pathway [Figure 1], first, GABA-transaminase converts GABA into succinic semialdehyde, which in turn is metabolized by SSADH into succinic acid that enters the Krebs cycle. If SSADH is absent, GABA transamination into succinic semialdehyde is followed by its conversion into γ-hydroxybutyric acid (GHB) through the GHB dehydrogenase, leading to higher endogenous GHB concentrations that are neurotoxic. A persistent increased excretion of urinary GHB is the biochemical marker of SSADH deficiency. The clinical phenotype includes, in addition to ASD, developmental delay, intellectual disability, hyperactivity, psychosis, epilepsy, ataxia, hypotonia, and hyporeflexia.,, We describe a girl with syndromic ASD affected by SSADH deficiency.
| Case Report|| |
The girl came to our attention for the first time at the age of 10 years and 3 months for a nonprogressive clinical picture of unknown etiology, with onset in the first year of life, mainly characterized by autistic behavior and intellectual disability.
Family history was negative for neuropsychiatric disorders. Prenatal period and delivery were normal. Since birth, the parents reported hypotonia, which over time has gradually disappeared. Up to the age of 2 and a half years, the sleep–wake rhythm was characterized by frequent nocturnal awakenings, although later it has normalized. She has shown a global developmental delay since the first year of life. Initially there was a deficit in gross and fine motility, the gait had ataxic characteristics. Over time, these motor characteristics have been attenuated. Regarding behavior, over time she presented a tendency to isolation, inability to follow social rules, attention deficit, lateral gaze, annoyance for various sound stimuli (motorcycles, dogs, carousel, bell, intercom, etc.), inability to maintain a conversation, and repetitiveness of the activities (continually watching Internet videos). A moderate intellectual disability was associated. The girl never presented epileptic seizures. A medical workup was performed to reach the etiological diagnosis. Karyotype, array comparative genomic hybridization, search for subtelomeric rearrangements, and molecular studies for fragile X syndrome, Prader–Willi syndrome, and Angelman syndrome, respectively, were all negative. Performance of brain 1.5T magnetic resonance imaging (MRI) at the age of 22 months has been reported as normal. At our first observation (age, 10 years and 3 months), neurological examination showed nonspecific dysmorphisms (broad forehead, oblique eyebrows, supraorbital swelling, stretched filter, and thin lips), joint laxity prevailing at the elbows, undefined handedness, atypical socio-communicative skills, and stereotypies. The electroencephalogram (EEG) during eye closure displayed exceedingly slow activities and a sharp theta rhythm in the left temporo-occipital regions, which were at least partially reduced by eye opening [Figure 2]. Leiter-R Scale showed a nonverbal intelligence quotient of 50, compatible with a mild/moderate intellectual disability. Autism Diagnostic Observation Schedule–Second Edition (ADOS-2), which is considered as the gold standard tool for ASD diagnosis, showed a result higher than the autism cut-off, with a moderate level of symptoms related to autism spectrum. Given the features of the girl’s clinical picture, we recommended a genetic counseling (see autism, intellectual disability, and nonspecific dysmorphisms) and a brain 3T MRI (see also EEG features). Genetic counseling led to perform a next-generation sequencing (NGS) multigene panel for neurological disorders, which revealed two variants for the ALDH5A1 gene: c.1226G>A (p.Gly409Asp), pathogenetic, and c.700C>T (p.Pro234Ser) for which in silico programs assume a pathogenetic meaning. Therefore, urinary organic acid analysis was carried out showing increased excretion of GHB, thus confirming the diagnosis of SSADH deficiency. The repetition of the brain MRI (3T) showed a T2-weighted signal hyperintensity in the globus pallidus bilaterally and a mild atrophy of the cerebellar vermis; also these findings were compatible with SSADH deficiency. At our last observation (age, 13 years and 3 months), the clinical picture of the girl was stable.
|Figure 2: Electroencephalogram recording during wakefulness at the age of 10 years 3 months. The black arrow indicates when the girl closes her eyes, which is explained in detail in the text|
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| Discussion|| |
The girl we reported was affected by a syndromic ASD, suggested by the presence of aspecific dysmorphisms. These clinical features have led us to carry out further investigations aimed at the etiological diagnosis, in addition to those previously performed that had not produced significant results. An NGS multigene panel for neurological disorders showed that the girl had SSADH deficiency, confirmed by urinary organic acid analysis. Compared to the classic description of this deficit, our patient presented a less severe picture. In fact, she had no epilepsy, and her neuromotor signs were soft, and over time they became less evident. One of the advantages of the increasing use of NGS multigene panels is the possibility of diagnosing even ASD cases with a genetic disease characterized by a milder or atypical symptomatology that would therefore risk being misdiagnosed. In this regard, our case report suggests that the real prevalence of SSADH deficiency may have been underestimated so far. As can be easily understood, the use of NGS multigene panels could increase the number of cases with syndromic ASD for which the etiological diagnosis is known. Obviously, knowing precisely the etiology of a syndromic case is very important because it can give suggestions on possible therapies and shed light on prognosis, but it also plays an essential role when providing genetic counseling to the family. As for the pharmacological therapy of SSADH deficiency, vigabatrin is an irreversible GABA-transaminase inhibitor preventing the metabolization of GABA into GHB. Despite this promising theoretical premise, treatment with vigabatrin produced uncertain results in these patients, and at the same time, it could cause important side effects., Other therapeutic strategies are being studied, including GHB receptor inhibitors. Returning to our case, this underlines the utility of EEG in the medical workup of patients with neurodevelopmental disorders, even in the absence of epileptic seizures. In fact, also the unusual EEG pattern we recorded, although not clearly pathological and even less specific to a given syndrome, led us to continue the etiological investigations.
In conclusion, this case report emphasizes the importance of considering, in a patient with syndromic ASD, the possible diagnosis of SSADH deficiency, even when all its typical signs are not present. Nowadays, the use of NGS multigene panels, as suggested by our case report, could facilitate the etiological diagnosis in individuals with syndromic ASD.
We would like to thank Cecilia Baroncini for linguistic support.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 5th ed (DSM-5). Washington, DC: American Psychiatric Association; 2013.
Sztainberg Y, Zoghbi HY Lessons learned from studying syndromic autism spectrum disorders. Nat Neurosci 2016;19:1408-17.
Pearl PL, Gibson KM, Acosta MT, Vezina LG, Theodore WH, Rogawski MA, et al
. Clinical spectrum of succinic semialdehyde dehydrogenase deficiency. Neurology 2003;60:1413-7.
Trevelyan AJ, Schevon CA How inhibition influences seizure propagation. Neuropharmacology 2013;69:45-54.
Pearl PL, Parviz M, Vogel K, Schreiber J, Theodore WH, Gibson KM Inherited disorders of gamma-aminobutyric acid metabolism and advances in ALDH5A1 mutation identification. Dev Med Child Neurol 2015;57:611-7.
Malaspina P, Roullet JB, Pearl PL, Ainslie GR, Vogel KR, Gibson KM Succinic semialdehyde dehydrogenase deficiency (SSADHD): pathophysiological complexity and multifactorial trait associations in a rare monogenic disorder of GABA metabolism. Neurochem Int 2016;99:72-84.
Vogel KR, Pearl PL, Theodore WH, McCarter RC, Jakobs C, Gibson KM Thirty years beyond discovery—clinical trials in succinic semialdehyde dehydrogenase deficiency, a disorder of GABA metabolism. J Inherit Metab Dis 2013;36:401-10.
Mizrahi EM Avoiding the pitfalls of EEG interpretation in childhood epilepsy. Epilepsia 1996;37:S41-51.
[Figure 1], [Figure 2]