Succinic semialdehyde dehydrogenase (SSADH) deficiency or 4-Hydroxybutyric Aciduria is an autosomal recessive inherited disorder of amma-aminobutyric acid (GABA) degradation. It is characterized by developmental delay, infantile-onset hypotonia, cognitive impairment language deficit, and ataxia. Epilepsy, aggression, Hyperkinetic behavior, hallucinations, and sleep disturbances have been described in about half of the patients, more frequently in older individuals. Its management is largely symptomatic, conducted at the treatment of seizures and neurobehavioral disorder. We present two girls with chief complaint of hypotonia and developmental delay how referred to department of Pediatrics (Ghaem hospital), Mashhad, Iran

Asma Javid

Farnoosh Ebrahimzadeh

Mehran Beiraghi Toosi

Nahid Donyadideh

Narges Hashemi

Rahim Vakili

Somayeh Hashemian

Directory of Open Access Journals

 
 
Int J Pediatr, Vol.6, N.7, Serial No.55, Jul. 2018                                                                                             7861 
Case Report (Pages: 7861-7865) 
 
http:// ijp.mums.ac.ir 
 
 4-Hydroxybutyric Aciduria as a Rare Presentation of Global 
Developmental Delay in Children:  Case Report of Two Different 
Patients 
Rahim Vakili1, *Mehran Beiraghi Toosi2, Asma Javid3, Nahid Donyadideh2, Farnoosh 
Ebrahimzadeh4, Narges Hashemi2, Somayeh Hashemian11 
 
 
1Department of Pediatric Endocrinology, Emam Reza Hospital, Faculty of Medicine, Mashhad University of 
Medical Sciences, Mashhad, Iran.  
2Department of Pediatric Neurology, Ghaem Hospital, Faculty of Medicine, Mashhad University of Medical 
Sciences, Mashhad, Iran. 
3Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran. 
4Department of Internal Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, 
Iran. 
 
 
 
Abstract 
      Succinic semialdehyde dehydrogenase (SSADH) deficiency or 4-Hydroxybutyric Aciduria is an 
autosomal recessive inherited disorder of amma-aminobutyric acid (GABA) degradation. It is 
characterized by developmental delay, infantile-onset hypotonia, cognitive impairment language 
deficit, and ataxia. Epilepsy, aggression, Hyperkinetic behavior, hallucinations, and sleep disturbances 
have been described in about half of the patients, more frequently in older individuals.  
Its management is largely symptomatic, conducted at the treatment of seizures and neurobehavioral 
disorder. We present two girls with chief complaint of hypotonia and developmental delay how 
referred to department of Pediatrics (Ghaem hospital), Mashhad, Iran. 
Key Words: Child, Developmental delay, 4-Hydroxybutyric Aciduria, Hypotonia.  
 
 
*Please cite this article as: Vakili R, Beiraghi Toosi M, Javid A, Donyadideh N, Ebrahimzadeh F, Hashemi N, et 
al. 4-Hydroxybutyric Aciduria as a Rare Presentation of Global Developmental Delay in Children:  Case Report 
of Two Different Patients. Int J Pediatr 2018; 6(7): 7861-65. DOI: 10.22038/ijp.2018.27462.2367 
 
 
 
 
 
 
 
 
                                                 
Corresponding Author: 
Mehran Beiraghi Toosi (M.D), Department of Pediatric neurology. Ghaem hospital, Faculty of Medicine, 
Mashhad University of Medical Sciences, Mashhad, Iran.  
E-mail: beiragitoosimehran@gmail.com 
Received date: Dec.18, 2017; Accepted date: Mar.12, 2018       
Rare Cause of Global Developmental Delay in Children 
Int J Pediatr, Vol.6, N.7, Serial No.55, Jul. 2018                                                                                             7862 
1- INTRODUCTION 
       Succinic semialdehyde dehydrogenase 
(SSADH) deficiency or 4-Hydroxybutyric 
Aciduria is an autosomal recessive 
inherited disorder of GABA degradation 
(1). GABA converts to succinate by 
combination of SSADH and GABA 
transaminase. The absence of SSADH 
leads to the transformation of GABA to γ-
Hydroxybutyric acid (GHB) (2-4) . The 
incidence of this disorder is unknown. A 
study of 182 patients from 40 countries 
determine the incidence of SSADH 
deficiency, with the most number of 
patients noted from the USA (24%), 
Turkey (10%), China (7%), Saudi Arabia 
(6%), and Germany (5%) (5).  
4-Hydroxybutyric Aciduria is 
characterized by developmental delay, 
infantile-onset hypotonia, cognitive 
impairment language deficit, and ataxia. 
Epilepsy, aggression, hyperkinetic 
behavior, hallucinations, and sleep 
disturbances have been described in about 
half of the patients, more frequently in 
older individuals. Basal ganglia signs 
including dystonia, choreoathetosis, and 
also myoclonus have been expressed in a 
minority of patients with earlier-onset and 
severe ones (6, 7).  
SSADH deficiency is diagnosed by 
checking levels of organic acids in urine 
(increased concentrations of 4-
hydroxybutyric acid (4-HBA) in urine (i.e., 
4-hydroxybutyric aciduria), measurement 
the activity of the SSADH enzyme in 
white blood cells and molecular genetic 
testing (identification of biallelic 
pathogenic variants in aldehyde 
dehydrogenase 5 family member A1 
[ALDH5A1]) (6, 8, 9). 4-Hydroxybutyric 
acid has been found in the urine of the all 
studied patients (10).The amounts excreted 
varied from 170 to340 mmol/mol 
creatinine. Concentration in urine have 
ranged from 2 fold to 5oo fold the normal 
level (11). Management is largely 
symptomatic, conducted at the treatment of 
seizures and neurobehavioral disorder (12, 
13). 
2- CASE REPORTS 
2-1. Case.1 
      N.K, an Iranian girl born to 
consanguineous parents (cousin), 
presented at 4.5 years of age for evaluation 
of failure to thrive and hypotonia since the 
age of 4 months (Figure.1). She had one 
sibling who was an eight-year old healthy 
girl and had no developmental problems. 
Her mother had an uncomplicated 
pregnancy. She was a full term baby with 
birth weight of 2,700gr, birth length of 
45cm, birth head circumference of 33cm 
and normal Apgar score. She admitted at 
hospital in the third day of life with chief 
complaint of poor feeding but no 
remarkable abnormal studies. She also had 
one hypoglycemic attack one year ago. 
Developmentally, at 54 months, she could 
not say any words but babbling, and had 
head drop until 12 months of age. She 
could seat without support at 18 months 
and walk alone in 30 months. Physical 
examination revealed a weight of 16 
kilograms, head circumference of 48cm 
and length of 103cm.  
No organomegaly were noticed. 
Neurological examination results show 
mild hypotonia (low muscle tone), and 
decreased deep tendon reflexes. No ataxia 
was detected. She didn’t have any history 
of seizure. The patient’s plasma showed 
normal Ammoniac (67 µmol/L), and 
lactate (12 mg/dl). Tandem mass 
spectrometry (MS/MS), high-performance 
liquid chromatography (HPLC) for serum 
amino acids and Urine sugar thin-layer 
chromatography (TLC) were normal. The 
concentration of Glycosaminoglycans 
(GAGs) or mucopolysaccharides in urine 
was 15.1 mg/mmol creat (normal range 5.2 
to 10.6). The organic acids in her urine 
showed an elevated 4-Hydroxybutyric 
Acid (450 mmol/mol creatinine, normally 
Vakili et al. 
Int J Pediatr, Vol.6, N.7, Serial No.55, Jul. 2018                                                                                             7863 
not detected). Electromyography (EMG) 
and nerve conduction velocity (NCV) 
tests, Auditory Brainstem 
Response (ABR) test and brain computed 
tomography scan were normal. Brain 
Magnetic Resonance Imaging (MRI) 
shows unspecified personality in white 
matter of right parietal lobe (Figure.2). 
Also, Electroencephalogram (EEG) 
showed unspecific changes. 
 
Fig.1: A 4.5-year-old with 4-Hydroxybutric Aciduria. 
  
Fig.2: Brain Magnetic Resonance Imaging: unspecified hypersignal in white matter of right parietal 
lobe. (A) Axial view, Fluid Attenuated Inversion Recovery (flair) sequence (B) coronal view, T2 - 
weighted sequence.  
Rare Cause of Global Developmental Delay in Children 
Int J Pediatr, Vol.6, N.7, Serial No.55, Jul. 2018                                                                                             7864 
2-2. Case.2 
K.K. presented at 4 years of age for 
evaluation of developmental delay and 
hypotonia (Figure.3). She was the first 
child of consanguineous parents from Iran. 
She was a 32 weeks’ preterm baby with 
birth weight of 1,560gr, birth length of 
41cm and birth head circumference of 
32cm. At birth she was admitted at 
neonatal intensive care unit (NICU) for 17 
days, and discharged without any 
complication. At 12 months, the infant had 
a probable seizure and her motor 
development was retard. At examination in 
4 years old, her weight was 13.5kg, height 
was 100 cm, and head circumference was 
47 cm. She had autistic spectrum disorder 
and had bilateral ptosis, oculomotor 
apraxia, increased deep tendon reflexes, 
mild dystonia and stereotypy. No 
organomegaly was detected. The patient’s 
plasma showed normal Ammonia (89 
µmol/L) and lactate (11.5 mg/dl). Tandem 
mass spectrometry (MS/MS), high-
performance liquid chromatography 
(HPLC) for serum aminoacids and Urine 
sugar thin-layer chromatography (TLC) 
were normal. The organic acids in her 
urine showed an elevated Lactic acid (487 
mmol/mcl creatinine, 
normal<158mmol/mcl creatinine), an 
elevated 3-Hydroxybutyric acid (83.9 
mmol/mcl creatinine, normal < 5.8 
mmol/mcl creatinine), and an elevated 4-
Hydroxybutanoic Acid (41.9 mmol/mol 
creatinine, normally not detected). MRI 
was normal. She had mildly abnormal 
electroencephalogram (EEG).  
 
 
Fig.3: The index patient with 4-Hydroxybutyric Aciduria. 
3- DISCUSSION 
     In this case report, we described two 
patients with 4-Hydroxybutyric Aciduria 
who initially presented with developmental 
delay and hypotonia. They had nonspecific 
clinical features witch could astound the 
correct diagnosis. Patients with 4-
Hydroxybutyric Aciduria do not manifest 
the regular concomitant of an inborn error 
of metabolism. There was no 
hyperammonemia, metabolic acidosis, 
growth retardation, episodic vomiting or 
lethargy that often seen in other inborn 
Vakili et al. 
Int J Pediatr, Vol.6, N.7, Serial No.55, Jul. 2018                                                                                             7865 
error of metabolism. Although urine 
mucopolysaccharides (MPS) in urine was 
elevated in the first girl, because it does 
not match with clinical signs the diagnosis 
was ruled out. So it is important to match 
the clinical and para clinical findings to get 
the true diagnosis and keep in mind that 
we must check levels of organic acids in 
urine in any child with hypotonia and 
developmental delay without any reason. 
4- CONCLUSION 
     Our suggestion would be exact, 
quantitative, organic acid analysis be 
ordered for any patient presenting with 
hypotonia and motor, mental or language 
delay of unknown cause. We think that 
expansion the use of organic acid analysis 
will lead to increase the diagnosis of 
SSADH deficiency, which will afford a 
more definite representation of the disease 
frequency. As additional patients are 
diagnosed, we should have a better 
perceptive of both the metabolic and 
clinical profile of SSADH deficiency. 
5- CONFLICT OF INTEREST: None. 
6- REFERENCES 
1. Jakobs C, Jaeken J, Gibson K. 
Inherited disorders of GABA metabolism. 
Journal of inherited metabolic disease. 
1993;16(4):704-15. 
2. Pearl PL, Novotny EJ, Acosta MT, 
Jakobs C, Gibson KM. Succinic semialdehyde 
dehydrogenase deficiency in children and 
adults. Annals of neurology. 2003;54(S6):S73-
S80. 
3. Gibson KM, Sweetman L, Nyhan WL, 
Jakobs C, Rating D, Siemes H, et al. Succinic 
semialdehyde dehydrogenase deficiency: an 
inborn error of gamma-aminobutyric acid 
metabolism. Clinica chimica acta. 
1983;133(1):33-42. 
4. Paggiaro P, Bacci E. Montelukast in 
asthma: a review of its efficacy and place in 
therapy. Therapeutic advances in chronic 
disease. 2010: 2040622310383343. 
5. Attri SV, Singhi P, Wiwattanadittakul 
N, Goswami JN, Sankhyan N, Salomons GS, 
et al. Incidence and Geographic Distribution of 
Succinic Semialdehyde Dehydrogenase 
(SSADH) Deficiency. JIMD 
Rep. 2017;34:111-115. doi: 
10.1007/8904_2016_14. Epub 2016 Nov 5. 
6.      Pearl PL, Novotny EJ, Acosta MT, 
Jakobs C, Gibson KM. Succinic semialdehyde 
dehydrogenase deficiency in children and 
adults. Annals of neurology. 2003 Jan 
1;54(S6). 
7. Gordon N. Succinic semialdehyde 
dehydrogenase deficiency (SSADH) (4-
hydroxybutyric aciduria, γ-hydroxybutyric 
aciduria). European Journal of Paediatric 
Neurology. 2004;8(5):261-5. 
8. Gibson KM, Christensen E, Jakobs C, 
Fowler B, Clarke MA, Hammersen G, et al. 
The clinical phenotype of succinic 
semialdehyde dehydrogenase deficiency (4-
hydroxybutyric aciduria): case reports of 23 
new patients. Pediatrics. 1997;99(4):567-74. 
9. Gibson K, Aramaki S, Sweetman L, 
Nyhan W, DeVivo D, Hodson A, et al. Stable 
isotope dilution analysis of 4‐ hydroxybutyric 
acid: An accurate method for quantification in 
physiological fluids and the prenatal diagnosis 
of 4‐ hydroxybutyric aciduria. Biological 
Mass Spectrometry. 1990;19(2):89-93. 
10. Kumari C, Varughese B, Ramji S, 
Kapoor S. Liquid–Liquid Extraction and Solid 
Phase Extraction for Urinary Organic Acids: A 
Comparative Study from a Resource 
Constraint Setting. Indian Journal of Clinical 
Biochemistry. 2016;31(4):414-22. 
11. Li X, Ding Y, Liu Y, Zhang Y, Song 
J, Wang Q, et al. Succinic semialdehyde 
dehydrogenase deficiency of four Chinese 
patients and prenatal diagnosis for three 
fetuses. Gene. 2015;574(1):41-7. 
12. Gibson KM, Gupta M, Pearl PL, 
Tuchman M, Vezina LG, Snead OC, et al. 
Significant behavioral disturbances in succinic 
semialdehyde dehydrogenase (SSADH) 
deficiency (gamma-hydroxybutyric aciduria). 
Biological psychiatry. 2003;54(7):763-8. 
13. Rahbeeni Z, Ozand P, Rashed M, 
Gascon G, Al Nasser M, Al Odaib A, et al. 4-
Hydroxybutyric aciduria. Brain and 
Development. 1994;16:64-71. 


4-Hydroxybutyric Aciduria as a Rare Presentation of Global Developmental Delay in Children: Case Report of Two Different Patients

http://ijp.mums.ac.ir/article_10215_3b4d3cbf56f4970fa7f5f300bdc030bb.pdf

4-Hydroxybutyric Aciduria as a Rare Presentation of Global Developmental Delay in Children: Case Report of Two Different Patients

Abstract

Similar works

Full text

Available Versions

Directory of Open Access Journals