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Screening Inherited Metabolic Disorder in Children with Intellectual Disability and Epilepsy/Zeka Geriligi ve Epilepsisi Olan Cocuklarda Kalitsal Metabolik Hastalik Taramasi.


Inherited metabolic disorders (IMDs) are not common causes of epilepsy and intellectual disability (ID). IMDs should be considered in the presence of neonatal seizures, neonatal or infantile deaths with unknown etiology, affected family members, parental consanguinity, macrocephaly or microcephaly, hydrops fetalis, progressive global psychomotor retardation, multisystem involvement such as cardiomyopathy, hepatosplenomegaly, cataract and muscle weakness, and characteristic magnetic resonance imaging findings such as cerebral and/or cerebellar atrophy, abnormal myelination and striatal necrosis (1,2,3,4). Seizures may be a part of a more complex neurologic presentation or sometimes only a feature of IMDs. Some IMDs (40-60%) can lead to isolated or recurrent convulsions (3).

ID, which is also known as mental retardation, is characterized by impairment of cognitive functions, adaptive behavior and life skills with limitations of learning, and presentation before age 18 years. In addition, children younger than 6 years are considered to have global developmental delay (GDD) if they perform more than 2 SDS below age-matched peers. GDD affects 1-3% of children aged under 6 years, and there are 2-3% of patients with ID in different populations (5,6). Global psychomotor retardation without other potential explanations may be suggestive of an IMD. In the absence of clues for other common causes of GDD/ID, the study of metabolic tests is recommended. Focused or sequential metabolic testing can increase the diagnostic rates up to 14% (7).

Treatments of some IMDs include dietary therapy, essential amino acid and vitamin supplementation, substrate inhibition and reduction therapy, enzyme replacement therapy, hematopoietic stem cell transplantation, and gene therapy. Therefore, early recognition is very important. In addition, identification of non-treatable causes is beneficial to the individual's family and allows genetic counseling (8).

The aim of this study was to explore the benefits of screening for IMDs in patients with epilepsy and GDD/ID with mild/moderate and non-specific neurologic findings.

Materials and Methods

This was a retrospective single-center clinical study. The medical records of 1100 patients who were investigated for IMDs between March 2014 and June 2017 were evaluated. Detailed disease histories, age, sex, and physical examinations were recorded in a form.

Inclusion criteria: Five hundred patients with epilepsy and GDD/ID with mild/moderate and non-specific neurologic findings were enrolled in the study.

Exclusion criteria: Patients with a specific genetic syndrome or neurologic disease, central nervous system (CNS) infection or CNS tumor, and febrile convulsions were excluded from the study. Although multidrug-resistant convulsions, cerebral palsy, and infantile severe hypotonia indicate metabolic disorders, they were also excluded from the study because the aim of this study was to explore IMDs in epilepsy and GDD/ID with mild/moderate neurologic symptoms.

Laboratory investigations: Non-specific tests include complete blood count, electrolytes, glucose levels, liver transaminases, urea, creatinine, creatine phosphokinase, thyroid function tests, vitamin B12, serum ammonia, lactate, pyruvate levels and peripheral chromosome analysis. Specific metabolic tests consist of plasma and urine amino acid analysis, blood acyl carnitine analysis, biotinidase activity and urinary organic acid analysis. Urinary glycosaminoglycan levels, urine sulfide oxide, serum copper, ceruloplasmin and homocysteine levels were studied in selected cases. All molecular genetic analyses were performed using next-generation sequencing in patients diagnosed as having IMDs.

The study was approved by the Ethics Committee of Erciyes University, Medical Faculty (Protocol number: 2017/421).

Informed consent was given by all parents of children with IMDs.

Statistical Analysis

The IBM SPSS Statistics 24.0 statistical package program was used in the evaluation of the data. Parameters with abnormal distribution are expressed as median (25th percentile 75th percentile). Data are presented as counts, percentages, and minimum and maximum values.


Five hundred patients with epilepsy and GDD/ID whose physical examinations and metabolic investigations were complete, and who met the inclusion criteria of the study were enrolled. Among the 500 children, 293 were male and 207 were female. The sex ratio was 1.4/1 in favor of the males. The ages of patients ranged from 20 days to 18 years. One hundred sixty-five patients (33%) were evaluated for GDD/ID of unknown etiology. Two hundred sixty-eight patients (53.6%) were followed up for epilepsy, and 67 patients (13.4%) with epilepsy and GDD/ID. Three hundred three (90.4%) of the 335 patients with epilepsy were using single antiepileptic drugs, 32 (9.6%) were using two antiepileptic drugs. Denver Developmental Screening Test II records of 108 patients and intelligence tests of 84 patients were available. Intelligence quotient (IQ) of 50-70 was considered mild impairment, and an IQ of less than 50 was considered moderate-to-severe impairment. The characteristics of children investigated for IMDs are shown in Table 1.

IMDs were diagnosed in seven patients as follows: one patient was diagnosed as having Tyrosinemia type-2, one had Menkes disease, one had Mitochondrial disease, one had Hyperphenylalaninemia, two siblings were diagnosed as having 3-methylcrotonyl CoA carboxylase deficiency, and one had Phenylketonuria. The demographic and clinical findings of patients with IMDs are shown in Table 2 and the laboratory findings and prognoses of patients with IMDs are shown in Table 3. In this study, the prevalence of IMDs among patients with epilepsy and GDD/ID was 1.4%.


Seizures may be a part of a more complex neurologic presentation or sometimes only feature as IMDs. Mercimek-Mahmutoglu et al. (9) evaluated 150 patients who underwent lumbar puncture due to epilepsy and movement disorder. IMDs were diagnosed in 6 (4%) of 150 patients. Sixty-six (44%) of 150 patients had GDD and epilepsy. IMDs were found in 1/268 (0.37%) of patients with epilepsy and 2/67 (2.98%) of patients with epilepsy and GDD/ID in our study, similar to these findings.

ID is a heavy burden both on the individual and society because its effects continue for a lifetime and also patients with ID have increased morbidity and mortality (10). Therefore, it is very important to identify treatable IMDs. There are few studies regarding ID and IMDs. Treatable IMDs were identified in 1-5% of patients as the cause of ID in some reports (11,12). Treatable IMDs, which have been detected in our study, are phenylketonuria, tyrosinemia type 2, mitochondrial disorders, 3-methylcrotonyl CoA carboxylase deficiency, and Menkes disease.

Engbers et al. (13) evaluated 433 patients with neurodevelopmental disorders and showed that 3% of these patients had IMDs. IMDs were found in 4/165 (2.4%) of patients with GDD/ID in our study.

Papavasiliou et al. (14) evaluated 118 patients with unexplained developmental delay ages from 3 months to 13 years and found 16 (13.6%) patients with neurometabolic disorder. The higher rate of IMDs in this report was attributed to more specific testing being performed such as cerebrospinal fluid lactate, very long-chain fatty acids, and mitochondrial enzymes.

van Karnebeek and Stockler-Ipsiroglu (15) reported that non-targeting screening with plasma amino acids, total homocysteine, acyl carnitine profile, copper, ceruloplasmin, urine organic acid, purine and pyrimidines, creatine metabolites, oligosaccharides, and glycosaminoglycans identified 64% of treatable IMDs. Diagnosis of all our patients was performed using non-targeting screening. The blood acyl carnitine profile and amino acid analysis are very important in the first step of specific metabolic investigations, and LC/MS/MS analysis allows the diagnosis of a large number of IMDs alone.

Henderson et al. (16) screened 1087 patients with mental retardation and found phenylketonuria (PKU) in three patients, cystinuria in two patients, and Hartnup disease in one patient. The overall frequency of IMDs was found as 0.6%. In our study, the frequency of IMDs among patients with epilepsy and GDD/ID was 1.4%.

PKU is a well-known cause of ID. Papassin et al. (17) reported PKU in a patient with ID at 20 years of age, like our case. The frequency of PKU was reported as 1/1581 in 4744 children with mental retardation (18). The PKU frequency was 1/165 in patient with unexplained GDD/ID in our study.

The incidence of IMDs is remarkably high in the Turkish population, which is partially due to the high rate of consanguinity. A total of 572 cases with 12 different types of aminoacidopathies were detected in 10,800 Turkish children with ID (19). PKU (4.7%) and homocysteinuria (0.2%) were common causes of ID in this report. The detection of Hyperphenylalaninemia in one of seven patients diagnosed with IMD and the detection of PKU in one patient supports this study.

Sempere et al. (20) evaluated 944 patients with unexplained ID and reported three patients with cerebral creatine deficiency syndromes, one patient with adenylosuccinate lyase deficiency, and three patients with PKU.

Study Limitations

The limitation of this study is that it did not allow screening of creatine biosynthesis, gamma-aminobutyric acid catabolism, purine and pyrimidine metabolism, congenital glycosylation, and glucose transport defects, which can present with nonspecific ID.


Early diagnosis and treatment is very important, and also identification of non-treatable causes is beneficial to the affected individual's family and allows genetic counseling. The prevalence of IMDs is higher in countries with a high consanguinity ratio such as Turkey. The lack of regular screening in patients with mild/moderate and non-specific neurologic findings result in late diagnosis.


Ethics Committee Approval: The study was approved by the Ethics Committee of Erciyes University, Medical Faculty, (Protocol number: 2017/421).

Informed Consent: Consent form was filled out by all parents of cases diagnosed with inherited metabolic disorders.

Peer-review: Internally peer-reviewed.

Authorship Contributions

Surgical and Medical Practices: P.S.U., A.S.G., H.G.P., Concept: P.S.U., Design: P.S.U., A.S.G., Y.A.T., Data Collection or Processing: H.G.P., I.G., S.G., Analysis or Interpretation: M.K., F.K., Literature Search: P.S.U., I.G., Writing: P.S.U.

Conflict of Interest: The authors declare that there are no conflicts of interest.

Financial Disclosure: The author declared that this study received no financial support.


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[iD] Pembe Soylu Ustkoyuncu (1), [iD] Ahmet Sami Guven (2), [iD] Hatice Gamze Poyrazoglu (2), [iD] Songul Gokay (1), [iD] Fatih Kardas (3), [iD] Mustafa Kendirci (3), [iD] Ikbal Gokcek (4), [iD] Yasemin Altuner Torun (4)

(1) University of Health Sciences, Kayseri Training and Research Hospital, Clinic of Pediatric Nutrition and Metabolism, Kayseri, Turkey

(2) University of Health Sciences, Kayseri Training and Research Hospital, Clinic of Pediatric Neurology, Kayseri, Turkey

(3) Erciyes University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Nutrition and Metabolism, Kayseri, Turkey

(4) University of Health Sciences, Kayseri Training and Research Hospital, Clinic of Pediatrics, Kayseri, Turkey

Address for Correspondence/Yazsima Adresi: Pembe Soylu Ustkoyuncu MD, University of Health Sciences, Kayseri Training and Research Hospital, Clinic of Pediatric Nutrition and Metabolism, Kayseri, Turkey

Phone: +90 505 671 64 71 E-mail: ORCID:

Received/Gelifl Tarihi: 13.09.2018 Accepted/Kabul Tarihi: 14.02.2019

Table 1. The characteristics of the children investigated for inherited
metabolic disorders

                                Total number  (%)
                                of patients

Variables                       500           100
Sex distribution
Male                            293            58.6
Female                          207            41.4
GDD/ID                          165            33
Epilepsy                        268            53.6
Epilepsy and GDD/ID              67            13.4
DDST II (n=108)
Language development             19            17.60
Gross motor development          38            35.19
Retardation in two areas         12            11.11
Retardation in three areas       13            12.03
Retardation in all areas         26            24.07
Intelligence test score (n=84)
Borderline intelligence           7             8.33
Mild mental retardation          49            58.33
Moderate mental retardation      28            33.34

DDST II: Denver Developmental Screening Test II, GDD: Global
developmental delay, ID: Intellectual disability

Table 2. The demographic and clinical findings of the patients with
inherited metabolic disorders

Case  Age               Sex  Consanguinity  Clinical findings

1     8 months          M    (-)            Epilepsy, poor head control
                                            and hair changes
2     4 years           M    (+)            Complex partial seizure,
                                            mild ID in Stanford-Binet
                                            Intelligence Scale and
                                            intermittent photophobia
3     10 years 4        F    (-)            Headache, learning
                                            disability, attention
                                            deficit hyperactivity
                                            disorder (using
      months                                methylphenidate) and mild ID
                                            in WISC-R
4     9 years           M    (+)            Generalized tonic clonic
                                            seizures (using valproic
                                            acid) and mildly impaired
                                            concentration difficulty in
                                            recent months.
5     17 years          M    (+)            Poor school performance and
                                            mild ID in WISC-R
6     9 years 2 months  F    (+)            Convulsion and mild ID in
7     15 years          M    (+)            Learning disability and mild
                                            ID in the WISC-R

WISC-R: Wechsler Intelligence Scale for Children, ID: Intellectual

Table 3. The laboratory findings and prognosis of the patients with
inherited metabolic disorders

Case  Laboratory findings                     Cranial MRI findings

1     Pili torti,                             Diffuse cerebral and
      low serum                               cerebellar atrophy in
      ceruloplasmin and                       MRI, vascular tortuosity
      copper level (*)                        in middle cerebral and
                                              vertebrobasilar arteries
                                              in cranial MRA
2     Elevated plasma                         Normal
      tyrosine and N-acetyl
      tyrosine level in
      urinary organic acids
      analysis ([dagger])
3     Basic metabolic tests                   Hyperintense signal
      were normal                             changes in the cerebellum
                                              close to the dentate
                                              nucleus and subcortical
                                              deep white matter in the
                                              cerebral hemispheres
4     Plasma phenylalanine                    Normal
      level was 524 [micro]mol/L
5     Plasma phenylalanine                    Hyperintense areas
      level was 1836 [micro]mol/L             adjacent to posterior horn
                                              of both lateral ventricles
6     C5-OH level elevated                    Normal
      in LC/MS/MS analysis ([double dagger])
7     C5-OH level elevated                    Normal
      in LC/MS/MS analysis ([section])

Case  Mutation          Diagnosis

1     c.3352G>A in      Menkes disease
      ATP 7A gene
2     c.935T>C and      Tyrosinemia
      c.1223C>T in TAT  type 2
3     m.8860A>G in      Mitochondrial
      ATP6 gene         disease
4     Not performed     HFA (not
                        responsive to a
                        BH4 loading test)
5     c.782G>A          PKU (not
      in PAH gene       responsive to a
                        BH4 loading test)
6     Not performed     3-methylcrotonyl
                        CoA carboxylase
7     Not performed     3-methylcrotonyl
                        CoA carboxylase

Case  Prognosis

1     He is bedridden and he has a
      significant feeding difficulty
2     Seizures were under control
      after dietary therapy
3     Behavioral disorders improved
      partially with coenzyme Q10,
      carnitine and vitamins
4     Seizures were controlled after
      phenylalanine restricted diet
5     School performance is bad
      and is not fully following the
6     No improvement in behavior
      and recognition with leucine
      restricted diet and carnitine
7     School performance is not so
      bad (only using carnitine)

(*) Serum ceruloplasmin concentration was 0.08 g/L (normal range:
0.31-0.91) and serum copper was 22 [micro]g/dL (normal range: 50-155).
([dagger]) Plasma tyrosine concentration was 1450 [micro]mol/L (normal
range: 0-400) in plasma amino acid analysis. 4-OH phenyl acetic acid
concentration was 915 mmol/molCre (normal range: 6-24), 4-OH phenyl
lactic acid was 9298 mmol/molCre (normal range: 0-2) N-acetyl tyrosine
concentration was 719 mmol/molCre (normal range: 0-2) in urinary
organic acids analysis.
([double dagger]) C5-OH concentration was 9 [micro]mol/L (normal range:
0-1.2) in LC-MS analysis. 3-methylcrotonyl glycine level was 588.9
mmol/molCre (n<2), 3-hydroxyisovaleric acid concentration was 1410.5
mmol/molCre (n=0-46) and 4-hydroxyphenylacetic concentration was 1020
mmol/molCre (n=6-28) in urinary organic acid analysis.
([section]) C5-OH concentration was 24.8 [micro]mol/L (normal range:
0-1.2) in LC-MS analysis. 3-methylcrotonyl glycine concentration was
874 mmol/molCre (n<2), 3-hydroxyisovaleric acid value was 1778
mmol/molCre (n=0-46) in urinary organic acid analysis.
MRI: Magnetic resonance imaging, MRA: Magnetic resonance angiography,
HFA: Hyperphenylalaninemia, PKU: Phenylketonuria
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Title Annotation:Original Article / Ozgun Arastirma
Author:Ustkoyuncu, Pembe Soylu; Guven, Ahmet Sami; Poyrazoglu, Hatice Gamze; Gokay, Songul; Kardas, Fatih;
Publication:Turkish Journal of Neurology
Date:Sep 1, 2019
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