Open Access

Thirteen year retrospective review of the spectrum of inborn errors of metabolism presenting in a tertiary center in Saudi Arabia

Orphanet Journal of Rare Diseases201611:126

https://doi.org/10.1186/s13023-016-0510-3

Received: 3 July 2016

Accepted: 6 September 2016

Published: 15 September 2016

Abstract

Background

Inborn errors of metabolism (IEMs) are individually rare; however, they are collectively common. More than 600 human diseases caused by inborn errors of metabolism are now recognized, and this number is constantly increasing as new concepts and techniques become available for identifying biochemical phenotypes. The aim of this study was to determine the type and distribution of IEMs in patients presenting to a tertiary care center in Saudi Arabia. METHOD: We conducted a retrospective review of children diagnosed with IEMs presenting to the Pediatric Department of King Abdulaziz Medical City in Riyadh, Saudi Arabia over a 13-year period.

Results

Over the 13- year period of this retrospective cohort, the total number of live births reached 110,601. A total of 187 patients were diagnosed with IEMs, representing a incidence of 169 in 100,000 births (1:591). Of these, 121 patients (64.7 %) were identified to have small molecule diseases and 66 (35.3 %) to have large molecule diseases. Organic acidemias were the most common small molecule IEMs, while lysosomal storage disorders (LSD) were the most common large molecule diseases. Sphingolipidosis were the most common LSD.

Conclusion

Our study confirms the previous results of the high rate of IEMs in Saudi Arabia and urges the health care strategists in the country to devise a long-term strategic plan, including an IEM national registry and a high school carrier screening program, for the prevention of such disorders. In addition, we identified 43 novel mutations that were not described previously, which will help in the molecular diagnosis of these disorders.

Keywords

Inborn errors of metabolism IEMs Saudi Arabia Lysosomal Organic acidemia Mitochondrial Fatty acid oxidation defects

Background

Inborn errors of metabolism (IEMs) are defined as monogenic diseases that result in dysfunctional proteins encoded by different genes, which in many cases lead to loss of activity of the enzymes involved [1]. More than 600 different inborn errors of metabolism have been recognized up to this point, and this number is constantly increasing as new concepts and techniques become available for identifying biochemical phenotypes. IEMs are extremely heterogeneous making their classification a primary challenge. Several informal systems of classification currently exist. IEMs can be classified according to the organs involved, such as neurological or hepatic disorders or according to the organelle involved, such as mitochondrial, peroxisomal or lysosomal disorders. Disorders can also be classified according to the age of presentation ranging from neonatal onset to juvenile and adult onset. Because each of these approaches may depend upon the actual setting, no single classification is universally applied [2]. One common and informative classification system involves the classification of IEMs into small and large molecule disorders [3]. Small molecule IEMs have an acute intoxication presentation with a remitting-relapsing clinical course. These include organic acidemias, vitamin responsive disorders, urea cycle disorders, inborn errors of carbohydrates, haem synthesis defects, cholesterol biosynthesis defects, and amino acids and metal transport defects. Large molecule IEMs have a gradual and insidious progressive presentation. These include glycogen storage disorders, sphingolipidosis, mucopolysaccharidosis, oligosaccharidosis, mitochondrial disorders and congenital disorders of glycosylation [2]. The diagnosis of IEMs is mainly based on biochemical investigations, which include the screening of several metabolites in the blood, urine and cerebrospinal fluid (CSF); analysis of enzymatic activities, and molecular genetics testing.

The incidence of such disorders vary from country to country and from region to region. In one Australian study the incidence was reported to be 15.7 per 100,000 births whereas, in Italy, the reported incidence was 27 per 100,000 births [4, 5]. In the West Midlands region in the United Kingdom (UK), the incidence reached up to 1:784 and in British Columbia, Canada, the incidence was reported to be 1:2500 [6, 7].

These disorders are usually inherited as autosomal recessive disorders, explaining why IEMs are common in populations with a high rate of consanguineous marriages, such as Saudi Arabia. In Saudi Arabia, the rate of consanguineous marriages reaches up to approximately 60 % [8, 9].

Despite the high frequency of IEMs, apart from the eastern region study [10], only a few anecdotal epidemiological studies in Saudi Arabia have discussed the incidence, type and distribution of such devastating disorders. Most of the remaining reports in the literature were limited to case reports and case series. In this study, we report the incidence, type, and distribution of IEMs presenting to King Abdulaziz Medical City (KAMC) in the middle region of Saudi Arabia over 13 years. In addition, we identified 43 novel mutations.

Methods

King Abdulaziz Medical City (KAMC) is a tertiary center in Saudi Arabia, that commenced operations in 1983. The bed capacity is 715, and an average of 8500 births per year occur at the center. This medical city passed the requirements for accreditation under the Joint Commission International (JCI) standards with excellent performance in December 2006. The current study is a retrospective review of all cases at the Pediatric Department of King Abdulaziz Medical City (KAMC) in Riyadh, Saudi Arabia. The duration of the study was 13 years, from 01-01-2001 to 31-12-2014. All patients included were born during this period. The cases were identified according to medical records via diagnostic codes and the genetic division’s database. The study was approved by the research committee of King Abdullah International Medical Research Centre (KAIMRC) in Riyadh, Saudi Arabia.

The diagnostic algorithm starts by referring patients based on clinical suspicion to genetic/metabolic facility from other departments, and from positive new born screening (NBS) after 2011. All accepted cases undergo phenotype related screening biochemical investigations. Confirmation of diagnosis is then achieved either by measuring enzyme activity and/or by targeted molecular tests. In case of unrevealing confirmatory investigations or vague presentation, whole exome or whole genome sequencing is requested.

The diagnosis of each IEM was based on clinical and biochemical investigations, including analyses of ammonia, lactic acid, total homocysteine, plasma amino acids, the acylcarnitine profile, urine aminoacids, urine for organic acids, copper, ceruloplasmine levels, very long chain fatty acids, transferrin isoelectrofocusing, carbohydrate-deficient transferrin and urine for polyols.

DNA molecular genetic testing was performed in commercial clinical international labs including CENTOGENE, GeneDx, Emory Genetics, Cincinnati Children’s Hospital Medical Center, Bioscientia and Nijmegen Medical Center. All of the parents of the patients with IEMs were tested for carrier status.

Incidence was calculated by dividing the number of diagnosed cases by the number of total births during the study period and multiplying by 100,000 [11].

Results

Over the 13-year period of this retrospective cohort study, the total number of live births reached 110,601. A total of 187 patients were diagnosed with an IEM, resulting in an incidence of 169 in 100,000 births (1:591). Of these patients, 121 (64.7 %) were identified to have a small molecule disease (Table 1) and 66 (35.3 %) to have a large molecule disease (Table 2). The overall mean, median and range of age at diagnosis were 3.2 years, 1.2 years and from 1 day to 13 years respectively. Tables 1 and 2 show the type and distribution of IEMs from 2001 to 2014 and illustrate the estimated incidence per 100,000 live births for each group of disorders and the mean, median and range of age at diagnosis for each group. The lysosomal storage disorders (LSDs) were the most common diagnosed group, in general, and were observed in 39/187 patients (20.8 %). Sphingolipidoses represent the largest subgroup of the LSDs (22/39; 56.4 %), and GM1 gangliosidosis (infantile phenotype) was the most prevalent disorder. The second most common category was organic acidemias (34/187; 18.2 %), with propionic acidemia (PA) as the most common disorder in that group. Aminoacidopathies were diagnosed in 30/187 patients (16 %). Fatty acid oxidation defects (FAOD) were diagnosed in 5/187 patients (2.7 %), and the frequency of patients with urea cycle disorders (UCD) was 12/187 (6.4 %). The most common FAOD was very long-chain acyl-CoA dehydrogenase deficiency (VLCAD), while argininosuccinic aciduria was the most common UCD. Mucopolysaccharidoses (MPS) were diagnosed in 15/187 patients (8 %), with MPS VI as the predominant type. Fourty-three novel mutations were identified, and missense mutations were the most common type of mutations (Tables 3 and 4). All the listed novel mutations fit with the clinical features of the disease, biochemical biomarkers support genotype phenotype correlation and they segregate well within the patients and family members.
Table 1

Small-molecule disorders of IEMs in KAMC (2001–2014). Total numbers of live births (110,601)

Disease category

Number of cases diagnosed

Incidence per 100,000

Mean age at diagnosis

Median age at diagnosis

Range of age

Organic acidemias

34

30

1.8 years

60 days

1 day–10 years

Propionic acidemia

9

 

30.2 days

20 days

1 day–6 months

Methylmalonic acidemia

7

    

Mutase deficiency

5

    

Cobalamin A defect

1

    

Cobalamin C defect

1

    

Glutaric acidemia

3

    

3-hydroxy-3-methylglutaryl-CoA lyase deficiency

4

    

3-Methylcrotonylco A carboxylase deficiency

3

    

Biotinidase deficiency

3

    

3-Methylglutaconic Aciduria Type III

1

    

Ethylmalonic encephalopathy

1

    

B-ketothiolase deficiency

1

    

Isovaleric acidemia

1

    

Malonic aciduria

1

    

Aminoacidopathies

30

27

3.3 years

10.5 months

1 day–13 years

Homocystinuria

14

 

7 years

7.5 years

 

 • Classical

11

    

 • MTHFR deficiency

2

    

 • MAT deficiency

1

    

PKU

5

    

 • Classical

3

    

 • Non-PKU hyperphenylalaninemia

2

    

Biopterin Synthesis Defect PTPS deficiency

4

    

MSUD

5

    

Asparagine synthetase deficiency

2

    

Vitamins responsive disorders

18

16

5.7 years

5.5 years

6 months–10 years

Biotin Thiamine Responsive Basal Ganglia Disease

17

    

Pyridoxine-dependent epilepsy

1

    

Inborn Errors of Carbohydrates

12

11

3.1 years

1.3 years

1 week–7 years

Galactosemia

4

    

Transaldolase deficiency

6

    

Hereditary fructose intolerance

1

    

Fructose 1,6 bisphosphatase deficiency

1

    

Urea Cycle Disorders

12

11

12 days

7 days

1 day–30 days

Argininosuccinic Aciduria

8

    

Citrullinemia

4

    

Fatty Acid Oxidation Defects

5

4

1.4 years

2 days

2 days–7 years

VLCAD deficiency

3

 

21 days

2 days

2 days–60 days

MCAD deficiency

1

 

2 days

2 days

2 days

Carnitine uptake defect

1

 

7 years

7 years

7 years

Aminoacids transport defect

5

4

10 years

11 years

6–13 years

Cystinuria

5

    

Metal transport defect

2

2

8.5 years

8.5 years

7–10 years

Wilson disease

2

    

Disorders of Haem biosynthesis

2

2

12.5 years

12.5 years

12–13 years

Acute intermittent porphyria

2

    

Cholesterol biosynthesis defect

1

1

1 year

1 year

1 year

CHILD syndrome

1

    

Total

121

109

3.3 years

9 months

1 day–13 years

MTHFR methylenetetrahydrofolatereductase, MAT methionine adenosyltransferase, PKU phenylketonuria, MSUD maple syrup urine disease, VLCAD very long-chain acyl-CoA dehydrogenase, MCAD medium-chain acyl-CoA dehydrogenase, CHILD Congenital hemidysplasia with ichthyosiform erythroderma and limb defects, PTPS 6-Pyruvoyl-Tetrahydropterin Synthase

Table 2

Large-molecule disorders of IEMs in KAMC (2001–2014). Total numbers of live births (110,601)

Disease category

Number of cases diagnosed

Incidence per 100,000

Mean age at diagnosis

Median age at diagnosis

Range of age

Lysosomal Storage Diseases (LSD)

41

37

3.6 year

3 years

2 months–13 years

Sphingolipidosis

22

20

3.1 years

2 years

2 months–13 years

Fabry disease

3

    

Sandhoff disease

2

    

Niemann–Pick disease type B

1

    

Niemann–Pick disease type C

3

    

GM1 gangliosidosis (infantile phenotype)

4

    

Metachromatic leukodystrophy

3

    

Saposin B Deficiency

2

    

Krabbe disease

1

    

Mucopolysaccharidosis (MPS)

15

14

5 years

5 years

5 months–12 years

MPS I

1

    

MPS II

1

    

MPS IIIA

2

    

MPS IVA

5

    

MPS VI

6

    

Oligosaccharidosis

2

2

3 years

3 years

2–4 years

Mucolipidosis II

1

    

α-mannosidosis

1

    

Others

     

Neuronal ceroid-lipofuscinoses

3: 2 type 6, and 1 type 8

 

5.3

5

5–6 years

GSD II

2

 

3.1 months

3.1 months

1 week to 6 months

Glycogen storage diseases (GSD)

5

4

2.2 years

2 years

15 months–4 years

GSD III

1

    

GSD IV

1

    

GSD IX

3

    

Mitochondrial disorders

12

11

2.2 years

8 months

1 week–8 years

Leigh disease

3

    

Pyruvate dehydrogenase deficiency

2

    

Pyruvate carboxylase deficiency

2

    

Mitochondrial DNA depletion syndrome 3

1

    

Mitochondrial DNA depletion syndrome 5

1

    

Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1

1

    

3-Methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like

1

    

Primary Coenzyme Q10 deficiency type 5

1

    

Peroxisomal disorders

7

6

2 years

9 months

1 week–8 years

Primary hyperoxaluria type 1

5

    

Zellweger syndrome

1

    

Rhizomelic Chondrodysplasia Punctata

1

    

Congenital disorders of glycosylation (CDG)

1 (CDG 1 L)

1

8 years

8 years

8 years

Total

66

60

3.1 years

2 years

1 week–13 years

Table 3

Mutations for small molecule IEMs

Disease category

Disease

Gene

Reported mutations

Novel mutations

Founder Vs. Private

Type of mutation

Organic acidemias

Propionic acidemia

PCCA

 

c.425G > A(p. Gly142Asp)

Founder

Homozygous, missense

c.350G > A (p.Gly117Asp)

 

Private

 

PCCB

c.1050dupT

 

Private

Dupplication

Methylmalonic acidemia

MUT

 

c.329 A > G(p. Tyr110Cys)

Founder

Homozygous, missense,

c.1677-1G > C

 

Private

Splice

Cobalamin A Defect

MMAA

c.586C > T (p.Arg196*)

 

Private

Nonsense

Cobalamin C defect

MMACHC

c.394C > T (p. Arg132*)

 

Private

Nonsense

Glutaric acidemia

GCDH

c.1144G > A (p.Ala382Thr)

 

Private

missense

 

c.853-2A > G (IVS8-2A > G)

Private

Splice

 

c.278A > G (p.His93Arg)

Private

missense

3-hydroxy-3-methylglutaryl-CoA lyase deficiency

HMGCL

c.122G > A

 

Founder

missense

3-Methylcrotonyl CoA carboxylase deficiency

MCCC1

 

c.1808 dup A(p. p.Asn603 Lysfs*5)

Private

Homozygous, duplication

MCCC2

c.1147A > T (p.Lys383*)

 

Private

Nonsense

Biotinidase deficiency

BTD

c.755A > G (p.Asp252Gly)

c.1330G > C (p.Asp444His)

 

Private

Two heterozygous missense mutations in Exon 4

3-Methylglutaconic aciduria type III

OPA3

 

c.194delG(p. Gly65Alafs*7)

Private

Homozygous, deletion

Ethylmalonic encephalopathy

ETHE1

 

c.263 C > T(p. Ser88Leu)

Private

Homozygous, missense

B-Ketothiolase deficiency

ACAT1

 

c.412-419del(p. Gln138Tyrfs*36)

Private

Homozygous, deletion

Isovaleric acidemia

IVD

 

c.358C > T(p. Arg120X)

Private

Homozygous, nonsense

Malonyl-CoA decarboxylase deficiency

MLYCD

 

c.953_954delAG(p. Glu318Valfs*35)

Private

Homozygous, deletion

Aminoacidopathies

Homocystinuria

     

Classical

CBS

c.969G > A (p.Trp323Ter)

 

Founder

Homozygous missense

c.1006C > T (p.Arg336Cys)

 

Founder

Homozygous missense

MTHFR deficiency

MTHFR

c.680C > T (p.Thr227Met)

 

Private

 

MAT deficiency

MAT1A

 

c.1081G > T(p.Val361Phe)

Private

Homozygous, missense

PKU

PAH

c.1169A > G (p.Glu390Gly)

 

Private

Homozygous, missense

PTPS deficiency

PTPS

 

c.238A > G(p. Met80Val)

Founder

Homozygous, missense

c.169_171delGTG (p.Val57del)

 

Founder

Homozygous, deletion

MSUD

BCKDHA

 

c.347A > G(p. Asp116Gly)

Private

missense

c.905A > C (p.Asp302Ala)

 

Founder

missense

BCKDHB

 

c.674 T > C(p.Leu225Pro)

Private

missense

 

c.1144 T > C(p.Cys382Arg)

Private

Homozygous, missense

Asparagine synthetase deficiency

ASNS

 

c.1160A > G (p.Tyr377Cys)

Founder

Homozygous, missense

Vitamins responsive disorders

Biotin Thiamine Responsive Basal Ganglia Disease

SLC19A3

c.1264A > G (p.Thr422Ala)

 

Founder

Homozygous, missense

Pyridoxine-dependent epilepsy

ALDH7A1

c.877dupAA (p.Ser293Lysfs*22)

 

Private

Duplication

Inborn Errors of Carbohydrates

Galactosemia

GALT

c.691 C > T (p.Arg231Cys)

 

Founder

Homozygous, missense

c.404C > T (p.Ser135Leu)

 

Private

Homozygous, missense

c.563A > G (P.Gln188Arg)

 

Private

Homozygous, missense

Transaldolase Deficiency

TALDO1

c.793delC (p.Gln265ArgfsX56)

 

Founder

Deletion

Hereditary fructose intolerance

ALDOB

c.360_363delCAAA (p.Asn119LysfsX31)

 

Private

Deletion

Fructose 1,6 bisphosphatase deficiency

FBP1

c.114_119dup (p. Cys39_Thr40dup)

 

Private

Duplication

Urea cycle disorders

Argininosuccinic Aciduria

ASL

c.556C > T (p.Arg186Trp)

 

Founder

Missense

c.1060C > T (p.Q354X)

 

Founder

Nonsense

Citrullinemia type 1

ASS1

 

c.364-2A > G

Founder

Homozygous, intronic

c.370G > A (p.Asp124Asn)

 

Founder

Homozygous, missense

Fatty acid oxidation defect

VLCAD

ACADVL

 

c.494 T > C(Phe165Ser)

Private

Homozygous, missense

VLCAD

ACADVL

c.65C > A (p.Ser22*)

 

Founder

Nonsense

MCAD

ACADM

 

c.255 G > T(p.Gly119*);)

Private

Homozygous, nonsense

 

c.938 T > G(p.Phe313Cys

Private

Homozygous, missense

Carnitine uptake defect

SLC22A5

 

c.1385G > A(p. Gly462Asp)

Private

Homozygous, missense

Aminoacids transport defect

Cystinuria

SLC3A1

 

c.1711 T > A(p.Cys571Ser)

Founder

Homozygous, missense

c.1400 T > A (p.Met467Lys)

 

Private

 

SLC7A9

 

c.1166 C > T(p.Thr389Met)

Private

Homozygous, missense

Metal Transport Defect

Wilson disease

ATP7B

c.2230 T > C (p.Ser744Pro)

 

Founder

Homozygous, missense

Disorders od Haem biosynthesis

Acute Intermittent Poephyria

HMBS

c.760delC (p.Leu254X)

 

Founder

Nonsense

Cholesterol biosynthesis defect

CHILD syndrome

NSDHL

c.314C > T (p.Ala105Val)

 

Private

Homozygous, missense

PKU phenylketonuria, MSUD maple syrup urine disease, VLCAD very long-chain acyl-CoA dehydrogenase, MCAD medium-chain acyl-CoA dehydrogenase

Table 4

Mutations for large molecule IEMs

Disease category

Disease

Gene

Reported mutations

Novel mutations

Founder Vs. Private

Type of mutation

LSD

Sphingolipidosis

Fabry

GLA

c. 782G > T (p.Gly261Val)

 

Founder

Homozygous, missense

Sandhoff disease

HEXB

 

c.1169 + 3_1169 + 10delAAGTTGTT (p.Gly65 AlafsX7)

Private

Deletion

Niemann-Pick disease type B

SMPD1

c.1267 C > T (p.His423Tyr)

 

Founder

Homozygous, missense

Niemann-Pick disease type C

NPC1

 

c.2130 + 1G > A;

Founder

Homozygous, intronic

 

c.2443_2444delp.ser815Leufs*54

Private

deletion

GM1 gangliosidosis

GLB1

 

c.950G > A(p. Trp317*)

Private

Homozygous, nonsense

c.171C > G (p.Tyr57X)

 

Founder

Homozygous, missense

Metachromatic leukodystrophy

ARSA

 

c.1108-2A > G

Private

Homozygous, intronic

Saposin B deficiency

PSAP

c.722G > C (p.Cys241Ser

 

Founder

Homozygous, missense

Krabbe disease

GALC

 

c.396G > A(p.Trp132*)

Private

Homozygous, nonsense

 

Mucopolysaccharidosis (MPS)

MPSI

IDUA

 

c.1868 T > C(p. Leu623Pro)

Private

Homozygous, missense

MPSII

IDS

 

c.405A > C(p. Lys135Asn)

Private

Homozygous, missense

MPSIIIA

SGSH

 

c.664-13C > G

Private

Homozygous, intronic

c.535G > A (p.Asp179Asn)

 

Private

Homozygous, missense

MPS IVA

GALNS

c.120 + 1G > C (IVS1 + 1G > C)

 

Private

Homozygous, missense

c.860C > T (p.Ser287Leu)

 

Private

Homozygous, missense

c.697G > A (p.Asp233Asn)

 

Private

Homozygous, missense

MPSVI

ARSB

c.753C > G (p.Tyr251*)

 

Founder

Homozygous, nonsense

c.430A > G (p.His393ARG)

 

Founder

Homozygous, missense

c.1079 T > C (p. Leu360Pro)

 

Private

Homozygous, missense

Oligosaccharidosis

Mucolipidosis II

GNPTAB

c.3503_3504 delTC (p.Phex1172)

 

Private

Homozygous, deletion

α-mannosidosis

MAN2B1

c.1340A > T (p.Asp447Val)

 

Private

Homozygous, missense

Others

NCL type 6

CLN6

 

c.794_796del(p.Ser265del)

Private

Homozygous, deletion

c.794_796delCCT

 

Private

Homozygous, deletion

  

NCL type 8

CLN8

Homozygous deletion encompassing exon2

 

Private

Homozygous, deletion

GSDII

GAA

 

c.1431delT(p. lle477fs)

Private

Homozygous, deletion

   

c.1657C > T(p. Gln553*)

Private

Homozygous nonsense

Glycogen storage disease

GSDIII

AGL

 

c.4353G > T(p. Trp1451Cys);

Private

Homozygous, missense

GSDIV

GBE1

 

c.998A > T (p.Glu 333 Val)

Private

Homozygous, missense

GSD IX

PHKG2

c.130C > T (p.Arg44*)

 

Founder

Homozygous nonsense

PHKB

 

Deletion Exon 5 and 6

Private

Homozygous, deletion

Mitochondrial disorders

Leigh disease

MTATP6

m.8993 T > G (p.Leu156Arg)

 

Private

Homoplasmic, missense

COX15

c.649C > T (p.Arg217Trp)

 

Private

Homozygous, missense

Pyruvate dehydrogenase deficiency

PDHA1

c.1256_1259dup (p.Trp421Serfs*6)

 

Private

Heterozygous Duplication

PDHA1

 

c.1132C > T (p.Arg378Cys)

Private

Hemizygous missense

Pyruvate Carboxylase Deficiency

PC

 

c.3116_3126del (p.Leu1039Glnfs*7)

Private

Deletion

 

Mitochondrial DNA depletion syndrome 3

DGUOK

c. 617G > A (p. R206k)

 

Private

Homozygous, missense

Mitochondrial DNA depletion syndrome 5

SUCLA2

 

c.362_363del (p.Ile121Serfs*38)

Private

Deletion

Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 1

SCO2

c.2 T > C(p.Met1?)

 

Private

Homozygous, missense

3-Methylglutaconic aciduria with deafness, encephalopathy, and Leigh-like

SERAC1

c.438del (p.Thr147Argfs*22)

 

Private

Deletion

Primary CoenzymeQ10 deficiency type 5

COQ9

 

chr16_57485062C > T (p.His62Arg)

Private

Homozygous, missense

Peroxisomal disorders

Primary hyperoxaluria type 1

AGXT

c.187G > C (p.Gly63Arg)

 

Founder

Homozygous, missense

Zellweger syndrome

PEX5

c.1578 T > G (p.Asn526Lys)

 

Private

Homozygous, missense

Rhizomelic chondrodysplasia punctata type 1

PEX7

 

c.321_322delTA(p.Tyr107*)

Private

Homozygous, deletion

Congenital disorder of glycosylation (CDG)

CGD 1 L

ALG9

c.1075G > A (p.E359K)

 

Private

Homozygous, missense

Discussion

In this report, we describe the incidence of IEMs in a single tertiary center in the middle region of Saudi Arabia over more than a decade. We reported an incidence of 1:591 individuals, which is the highest incidence for IEMs reported to this point. Our study is the second epidemiological report after that of Moammar et al., 2010, who reported a incidence of 1:667 [10]. If we combine the two studies, the cumulative incidence is 1:635 births or 157 per 100,000, which is still one of highest reported incidence rates across the world. KAMC is one of the largest medical institutions in the Kingdom and is also a referral center; therefore to obtain a more accurate estimation of incidence of these disorders we have excluded the 69 patients who were diagnosed with IEM but not born at KAMC. If we combine the referred cases with those of patients born at the hospital, we obtain an incidence of 231.5 in 100,000 births (1:432).

Our study confirms the conclusions drawn by Moammar et al., 2010, LSDs are the most commonly identified group of disorders and organic acidemias are the most prevalent small molecule diseases. Our work also supports the notion that MPS VI is the most common type of mucopolysaccharidosis in Saudi Arabia. The results also support the wide variation in incidence of genetic diseases between Saudi Arabia and other parts of the world [12]. In our study for example the recorded number of PTPS exceeds the classical PKU which is reverse in Caucasian population [13]. This is more evident in PA, in which incidence in Saudi Arabia far exceeds the global incidence [14]. During the course of our study we discovered 9 new PA cases in our center, with incidence of 1 per 12,500 live births.

Our study showed unique phenotypes in comparison with the literature. Our three VLCAD patients for example had early presentation with severe phenotype ended with early death. Their genotype mutations were one novel missense mutation in exon 6, c.494 T > C (p.Phe165Ser) and the other two had previously reported nonsense mutation in exon 2, c.65C > A (p.Ser22*). Although these mutations are not clear null mutations [15], they resulted in severe phenotype. Alternatively, the most common phenotype in VLCAD is the milder late onset with the missense mutation p.Val283Ala being the most prevalent disease causing variant [15]. This reflect the poor genotype-phenotype correlation.

In this study the number of private mutations was almost double that of founder mutations, which support the previous report of Al-Owain et.al (2012) who noted that private mutations outweigh founder mutations in Saudi Arabia [12].

Interestingly, among the diseases discovered by our study, 35 diseases are amenable for treatment. Recent advances in early diagnostic tools like the expanded New Born Screening program list, which can detect 14 of the listed diseases, and the availability of treatment options like enzyme replacement therapy, opened new horizons for these patients and their families.

With the implementation of next generation sequencing (WES and WGS) we were able to solve many obscure cases. Additionally, new diseases and new variants might be discovered more easily. It is possible to see NGS a first line diagnostic tool in the near future.

The markedly high numbers of metabolic diseases in Saudi Arabia in general and in our center in particular, with mostly homogenous genotypes, paves the way for future collaboration with international parties, research centers and drug industry, to help providing treatment for our patients. This environment is ideal for wide spectrum of clinical trials of various phases, to speed up the process of new medications discovery.

The limitations of the presented cohort study are clear. These include the fact that the study is confined to a single center in one particular region and contains a small sample size; therefore, the internal and external validity of the study is threatened. Such a retrospective review increases the risk of selection and information biases. Therefore, the numbers mentioned in this study should be taken with caution until further larger studies confirm or refute such findings. The retrospective nature risks missing cases due to poor documentation. In addition, some patients with metabolic disorders may not be seen at the medical center due to early death prior metabolic intervention. In addition, cases with a relatively mild disease may never have presented to the specialized metabolic center, which also contributes to the bias inherent in this study. The variability in ages at diagnosis is attributed to the delay in referring cases to the metabolic facility from other departments, and these numbers should not reflect the expected age of presentation for the listed diseases.

The incredibly high rate of IEMs in Saudi Arabia compels the health care administration in the country to develop a long-term strategic plan for the prevention of such disorders. First, a national registry should be implemented, and through that registry, a determination of the most common IEM and most common mutations in the population can be made. Second, genetic screening of high school students by DNA molecular testing should be performed to identify carriers for the most common disorders in the Saudi population. Premarital molecular screening can help couples, who carry the same disease causing variants, to take informed decision regarding their marriage and the consequences of their decision. Such a strategy has proven to be effective in another population [16]. Finally, intensive educational campaigns aimed at the community through schools, TV, and web-based social media should be initiated.

Conclusion

In this study, we report the incidence, type, and distribution of IEMs presenting to King Abdulaziz Medical City (KAMC) in the middle region of Saudi Arabia over 13 years. We also identified 43 novel mutations in 37 genes. Our study emphasizes the high incidence of IEMs in the Saudi population and urges the health care administration in the country to develop a long-term strategic plan for the prevention of such disorders, including an IEMs national registry and a high school carrier screening program.

Abbreviations

CHILD: 

Congenital hemidysplasia with ichthyosiform erythroderma and limb defects

CSF: 

Cerebrospinal fluid

IEM: 

Inborn error of metabolism

IEMs: 

Inborn errors of metabolism

IRB: 

Institutional review board

JCI: 

Joint Commission International

KAIMRC: 

King Abdullah International Medical Research Centre

KAMC: 

King Abdulaziz Medical City

LSD: 

Lysosomal storage disorders

MAT: 

Methionine adenosyltransferase

MCAD: 

Medium-chain acyl-CoA dehydrogenase

MSUD: 

Maple syrup urine disease

MTHFR: 

Methylenetetrahydrofolate reductase

PKU: 

Phenylketonuria

SCAD: 

Small-chain acyl-CoA dehydrogenase

UCD: 

Urea cycle disorders

UK: 

United Kingdom

VLCAD: 

Very long-chain acyl-CoA dehydrogenase

Declarations

Acknowledgements

We would like to thank Prof. Dr. Ronald J.A. Wanders from Academic Medical Center, University of Amsterdam for his valuable contribution.

Funding

This research received no specific grant from any funding agency in the public, commercial or not-for-profit sectors’.

Availability of data and materials

Not applicable, as this study is a retrospective chart review over a long period and the data are scattered in several files. Any data will be available upon the request of the reviewers.

Authors’ contributions

MAF: performed the majority of the work associated with preparing, writing and submitting the manuscript and contributed to the clinical diagnosis and management of the patients from King Abdulaziz Medical City. MBM and MAH: summarized the clinical and molecular genetic data and contributed to the analysis part of the manuscript. AAO, AAF, MAB: edited the manuscript and contributed to the biochemical and molecular diagnosis of the patients summarized in the article. AAZ and WE: edited the manuscript. All of the authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

Informed consent to participate in the study was obtained from the parents of participants.

Ethics approval and consent to participate

The study was approved by the research committee of King Abdullah International Medical Research Centre (KAIMRC) in Riyadh, Saudi Arabia.

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Authors’ Affiliations

(1)
Department of Pediatrics, King Abdulaziz Medical City
(2)
King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City
(3)
Ministry of National Guard-Health Affairs (NGHA)
(4)
Department of Pathology, King Abdulaziz Medical City
(5)
Qassim University, College of Medicine, Department of Pediatrics
(6)
Division of Genetics, Department of Pediatrics King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City
(7)
Advanced Clinical Research Center, Shin-Yurigaoka General Hospital

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Copyright

© The Author(s). 2016

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