Indian J Pediatr DOI 10.1007/s12098-015-2003-0
SCIENTIFIC LETTER
Succinic Semialdehyde Dehydrogenase Deficiency Presenting as Autism Spectrum Disorder Maria Gogou 1,3 & Martha Spilioti 2 & Despoina Tramma 1 & Efimia Papadopoulou-Alataki 1 & Athanasios Evangeliou 1
Received: 28 April 2015 / Accepted: 16 December 2015 # Dr. K C Chaudhuri Foundation 2016
To the Editor: A 10-y-old boy with autism spectrum disorder (DSM IV criteria) and normal perinatal history presented to our outpatient clinic for investigation. Evaluation revealed declined fine motor development, moderate language development, repetitive behavior, attention deficit and hyperactivity. Common laboratory tests, electroencephalogram and Magnetic Resonance Imaging (MRI) of the brain were normal. The metabolic screening requested revealed an elevated concentration of 4-hydroxy-butyric acid in urine (60.8 mmol/mol creatinine of urine, normal values: 0). Genetic test revealed two pathogenic mutations in the ALDH5A1 gene, thus confirming diagnosis of succinic semialdehyde dehydrogenase deficiency (SSADHD). Treatment with vigabatrin was initiated without clinical improvement.
* Maria Gogou [email protected] 1
4th Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, General Hospital Papageorgiou, Thessaloniki, Greece
2
1st Department of Neurology, Aristotle University of Thessaloniki, University General Hospital AHEPA, Thessaloniki, Greece
3
Dimitriou Nika 44, 60, 100 Katerini, Greece
SSADHD is caused by mutations of the ALDH5A1 gene (6p22), resulting in dysfunction of the enzyme succinic semialdehyde dehydrogenase and accumulation of γ-aminobutyric acid, succinic semialdehyde and γhydroxybutyric acid. Clinical features include intellectual disability, seizures, hypotonia, ataxia and behavioral disturbances. Diagnosis is mainly based on urinary organic acid analysis and genetic testing [1]. MRI of the brain often demonstrates globus pallidii signal changes and cerebellar atrophy [2]. Clinical studies about the impact of vigabatrin, sodium valproate and taurine on clinical aspects of the disease have controversial results [1]. The patient presented autism as the only symptom. This raises the question if metabolic screening should be requested for children with autism spectrum disorder. Schiff et al. found that a routine metabolic screening does not contribute to the causative diagnosis of autism, as the prevalence of inborn metabolic errors in nonsyndromic autism may not be higher than in the general population [3]. On the other hand, in a Greek cohort study of 187 children with confirmed autistic features, who underwent detailed metabolic screening, specific metabolic biomarkers were revealed in 5 of them (2, 7 %) with therapeutic relevance [4]. The underlying cause of autism is often elusive with the exception of recognizable genetic syndromes [3]. The identification of a specific cause at an early age is important for initiating effective individualized intervention and permits genetic counseling.
Indian J Pediatr Table 1
Inborn errors of metabolism with autism phenotype as the main or only symptom
Disorder
Onset
Diagnostic Test
Additional Traits
Phenylketonuria
Neonatal
Phenylalanine in blood
Mental retardation, seizures
Creatine Deficiency syndromes
0–24 mo
Creatine in blood and urine
Mental retardation, extrapyramidal signs
Biotinidase deficiency Histidinemia
1st y At birth
Biotinidase in blood Histidine in plasma and urine
Ataxia, vision/hearing problems, skin rash, alopecia Speech problems, mental retardation, asymptomatic
Disorders of purine and pyrimidine metabolism Cholesterol Biosynthesis syndromes (Smith-Lemli-Opitz syndrome) Organic acidemias Dihydropyrimidine dehydrogenase deficiency
1st y >1st y
Uric acid in blood and 24 h urine Plasma cholesterol and 7-dehydrocholesterol Urine organic acids Urine organic acids
Psychomotor retardation, epilepsy Behavioral disturbances, poor speech, self-harm
Any age Any age
Therefore, screening for metabolic disorders focused on treatable inborn metabolic errors may be considered in children with autism of no obvious etiology [5] (Table 1).
References 1.
2. Acknowledgments Special acknowledgements to Dr. Gajja Salomons, Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands, for analysis of the ALDH5A1 gene.
3.
4. Conflict of Interest None. 5. Source of Funding None.
Epilepsy, behavioral problems, vomiting Microcephaly, delayed growth, seizures
Gahr M, Connemann BJ, Schönfeldt-Lecuona CJ, Freudenmann RW. Succinic semialdehyde dehydrogenase deficiency: an inheritable neurometabolic disease. Fortschr Neurol Psychiatr. 2013;81:154–61. Acosta MT, Munasinghe J, Pearl PL, et al. Cerebellar atrophy in human and murine succinic semialdehyde dehydrogenase deficiency. J Child Neurol. 2010;25:1457–61. Schiff M, Benoist JF, Aïssaoui S, et al. Should metabolic diseases be systematically screened in nonsyndromic autism spectrum disorders? PLoS ONE. 2011;6:e21932. Spilioti M, Evangeliou AE, Tramma D, et al. Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD). Front Hum Neurosci. 2013;7:858. Ghaziuddin M, Al-Owain M. Autism spectrum disorders and inborn errors of metabolism: an update. Pediatr Neurol. 2013;49:232–6.
SCIENTIFIC LETTER
Succinic Semialdehyde Dehydrogenase Deficiency Presenting as Autism Spectrum Disorder Maria Gogou 1,3 & Martha Spilioti 2 & Despoina Tramma 1 & Efimia Papadopoulou-Alataki 1 & Athanasios Evangeliou 1
Received: 28 April 2015 / Accepted: 16 December 2015 # Dr. K C Chaudhuri Foundation 2016
To the Editor: A 10-y-old boy with autism spectrum disorder (DSM IV criteria) and normal perinatal history presented to our outpatient clinic for investigation. Evaluation revealed declined fine motor development, moderate language development, repetitive behavior, attention deficit and hyperactivity. Common laboratory tests, electroencephalogram and Magnetic Resonance Imaging (MRI) of the brain were normal. The metabolic screening requested revealed an elevated concentration of 4-hydroxy-butyric acid in urine (60.8 mmol/mol creatinine of urine, normal values: 0). Genetic test revealed two pathogenic mutations in the ALDH5A1 gene, thus confirming diagnosis of succinic semialdehyde dehydrogenase deficiency (SSADHD). Treatment with vigabatrin was initiated without clinical improvement.
* Maria Gogou [email protected] 1
4th Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, General Hospital Papageorgiou, Thessaloniki, Greece
2
1st Department of Neurology, Aristotle University of Thessaloniki, University General Hospital AHEPA, Thessaloniki, Greece
3
Dimitriou Nika 44, 60, 100 Katerini, Greece
SSADHD is caused by mutations of the ALDH5A1 gene (6p22), resulting in dysfunction of the enzyme succinic semialdehyde dehydrogenase and accumulation of γ-aminobutyric acid, succinic semialdehyde and γhydroxybutyric acid. Clinical features include intellectual disability, seizures, hypotonia, ataxia and behavioral disturbances. Diagnosis is mainly based on urinary organic acid analysis and genetic testing [1]. MRI of the brain often demonstrates globus pallidii signal changes and cerebellar atrophy [2]. Clinical studies about the impact of vigabatrin, sodium valproate and taurine on clinical aspects of the disease have controversial results [1]. The patient presented autism as the only symptom. This raises the question if metabolic screening should be requested for children with autism spectrum disorder. Schiff et al. found that a routine metabolic screening does not contribute to the causative diagnosis of autism, as the prevalence of inborn metabolic errors in nonsyndromic autism may not be higher than in the general population [3]. On the other hand, in a Greek cohort study of 187 children with confirmed autistic features, who underwent detailed metabolic screening, specific metabolic biomarkers were revealed in 5 of them (2, 7 %) with therapeutic relevance [4]. The underlying cause of autism is often elusive with the exception of recognizable genetic syndromes [3]. The identification of a specific cause at an early age is important for initiating effective individualized intervention and permits genetic counseling.
Indian J Pediatr Table 1
Inborn errors of metabolism with autism phenotype as the main or only symptom
Disorder
Onset
Diagnostic Test
Additional Traits
Phenylketonuria
Neonatal
Phenylalanine in blood
Mental retardation, seizures
Creatine Deficiency syndromes
0–24 mo
Creatine in blood and urine
Mental retardation, extrapyramidal signs
Biotinidase deficiency Histidinemia
1st y At birth
Biotinidase in blood Histidine in plasma and urine
Ataxia, vision/hearing problems, skin rash, alopecia Speech problems, mental retardation, asymptomatic
Disorders of purine and pyrimidine metabolism Cholesterol Biosynthesis syndromes (Smith-Lemli-Opitz syndrome) Organic acidemias Dihydropyrimidine dehydrogenase deficiency
1st y >1st y
Uric acid in blood and 24 h urine Plasma cholesterol and 7-dehydrocholesterol Urine organic acids Urine organic acids
Psychomotor retardation, epilepsy Behavioral disturbances, poor speech, self-harm
Any age Any age
Therefore, screening for metabolic disorders focused on treatable inborn metabolic errors may be considered in children with autism of no obvious etiology [5] (Table 1).
References 1.
2. Acknowledgments Special acknowledgements to Dr. Gajja Salomons, Department of Clinical Chemistry, Metabolic Unit, VU University Medical Center, Amsterdam, The Netherlands, for analysis of the ALDH5A1 gene.
3.
4. Conflict of Interest None. 5. Source of Funding None.
Epilepsy, behavioral problems, vomiting Microcephaly, delayed growth, seizures
Gahr M, Connemann BJ, Schönfeldt-Lecuona CJ, Freudenmann RW. Succinic semialdehyde dehydrogenase deficiency: an inheritable neurometabolic disease. Fortschr Neurol Psychiatr. 2013;81:154–61. Acosta MT, Munasinghe J, Pearl PL, et al. Cerebellar atrophy in human and murine succinic semialdehyde dehydrogenase deficiency. J Child Neurol. 2010;25:1457–61. Schiff M, Benoist JF, Aïssaoui S, et al. Should metabolic diseases be systematically screened in nonsyndromic autism spectrum disorders? PLoS ONE. 2011;6:e21932. Spilioti M, Evangeliou AE, Tramma D, et al. Evidence for treatable inborn errors of metabolism in a cohort of 187 Greek patients with autism spectrum disorder (ASD). Front Hum Neurosci. 2013;7:858. Ghaziuddin M, Al-Owain M. Autism spectrum disorders and inborn errors of metabolism: an update. Pediatr Neurol. 2013;49:232–6.
