Indian Journal of Pediatrics (February 2022) 89(2):184–191

https://doi.org/10.1007/s12098-021-03958-4

CLINICAL BRIEF

Clinical and Genetic Spectrum of 50 Children with Inborn Errors

of Metabolism from Central India
Gouri Rao Passi1 · Akash Wakchaure1 · Shree Prakash Jaiswal2

Received: 21 January 2021 / Accepted: 6 August 2021/ Published online: 25 November 2021
© Dr. K C Chaudhuri Foundation 2021

Abstract
This is a single-center, retrospective analysis of children confirmed to have an inborn error of metabolism in the pediatric
department of a teaching hospital in central India. Patients were categorized as acute encephalopathy, developmental delay/
seizures, and neuroregression or organomegaly depending on their predominant phenotype. Of the 50 patients analyzed,
the commonest group was lysosomal storage disorders in 13 (26%), followed by organic acidurias - 8 (16%), mitochondrial
disorders - 5 (10%), urea cycle disorders, carbohydrate metabolism disorders, and amino acidopathies - 4 (8%) each, fatty
acid oxidation defects and neurotransmitter deficiency disorders - 3 (6%) each, and miscellaneous (8%). Genetic variations
were identified in 25 (50%). Acylcarnitine profiles and urine organic acids were diagnostic in 62.5% of children presenting as
acute encephalopathy, exome sequencing in 55.5% of children with neuroregression, and specific enzyme assay in 83.3% of
children with predominant organomegaly (83.3%). Children with developmental delay/seizures needed a wider range of tests.

Keywords Inborn errors of metabolism · Genetics · Diagnostic tests

Introduction Hospital, Indore, between 2015 and 2020 were retrieved.

Identifying inborn errors of metabolism (IEMs) is important
because many are eminently treatable [1]. In India, the abil-
ity to identify inborn errors of metabolism is improving [2].
Identifying the important inborn errors of metabolism will
help plan neonatal screening programs at a national level [3].
There have been reports of IEMs from various parts of India
but no large series from central India [4–9]. In this study, the
clinical and genetic data of children with IEMs from a single
center in Central India has been collated and the most useful
tests for diagnosis have been identified.
Material and Methods
This was a single-center, retrospective study from a teaching
hospital in Indore, in central India. Records of patients diag-
nosed with IEM in the Department of Pediatrics, Choithram
* Gouri Rao Passi
gouripassi@gmail.com
1
Department of Pediatrics, Choithram Hospital Research
Center, Indore, Madhya Pradesh 452014, India
2
Department of Pathology and Microbiology, Choithram
Hospital & Research Center, Indore, Madhya Pradesh, India
Clinical, biochemical, radiological, and genetic data were
analyzed. Tests utilized in making a diagnosis included
serum acylcarnitine profile (using MS/MS), urine organic
acids (Urine GC–MS), specific enzyme assays (fluorom-
etry on DBS), urinary glycosaminoglycans (GAGs) (using
dimethyl methylene blue dye binding method), magnetic
resonance imaging with spectroscopy, urinary pyrimidines
and purines (using HPLC), serum homocysteine, serum
copper and ceruloplasmin and genetic testing using next-
generation sequencing. Ethics clearance was taken from the
Institutional Ethics Committee.
Patients were classified into 4 categories depending on
the predominant clinical presentation—acute encepha-
lopathy, developmental delay/seizures, organomegaly, and
neuroregression. The yield of the simplest diagnostic test in
each category was assessed.
Results
A total of 50 patients (21 females) with ages ranging from
one day to 15 y were included into the study. Consan-
guinity was seen in 9 (18%) and a positive family history
was documented in 13 (26%). The commonest group of
disorders were lysosomal storage disorders in 13 (26%),
Table 1  Clinical and genetic features of children with IEM
Category Number Predominant Test which confirmed Genetic variations identified Type of variant Novel/Reported Segregation analysis
presentation the diagnosis variant

I. LSD
MPS 6 DD Elevated
GAG’s > 30 mg/mM
creatinine
GD 4 O Beta glucosidase Homozygous mutations Pathogenic Reported The 2 patients with
enzyme assay: lev- in GBA:c.1448 T>C; (ClinVar) variant c.1184C>T
els < 2 nmol/ml/h (p.Leu483Pro) & were siblings
c.1184C>T;(p.Ser395Phe) in
two patients each
NPD 1 O Sphingomyli- Compound heterozygous patho- Likely pathogenic Reported Not done
nase enzyme genic mutations in SMPD1 (ClinVar)
assay < 0.8 nmol/ gene:
ml/h c.1783_1784delCT;1804C>T;
Indian Journal of Pediatrics (February 2022) 89(2):184–191

(p.Ala597ProfsTer7);(Arg60
2Cys)
Sandhoff 1 N Beta hexosaminidase Homozygous variants (VOUS) VOUS Novel variant Not done
(A + B) enzyme in HEXB gene:c.T1081C;(p.
assay < 900 nmol/h/ Trp361Arg)
mg
Tay–Sachs 1 N Beta hexosamini-
dase A enzyme
assay < 60 nmol/h/
mg
II. Organic
acidurias
PA 3 E Urine organic acids
- elevated 3-OH
propionic acid,
propionyl glycine,
tiglylgycline, methyl
citric acid
MS/MS - elevated C3
acylcarnitine
MMA 2 E Urine organic acids
- elevated methyl
malonic acid along
with 3 OH propionic
acid and methyl
citric acid
MS/MS - elevated C3
acylcarnitine
185
Table 1  (continued)
186

Category Number Predominant Test which confirmed Genetic variations identified Type of variant Novel/Reported Segregation analysis
presentation the diagnosis variant

GA 1 2 E-1, N-1 Urine organic acids

- elevated glutamic
acid, glutaconic
acid, 3-OH glutamic
acid
MS/MS - elevated
glutarylcarnitine
C5DC
3HMG CoA lyase 1 E Urine organic acids -
elevated 3 methyl
glutaconic acid,
methyl glutaric
acid, 3 OH 3 methyl
glutaric acid
MS/MS - elevated
C5OH acylcarnitine
and C6DC acylcar-
nitine
III. Mitochondrial
disorders
Complex 1 defi- 2 N Case 1: Case 1: Compound het- Case 1: Likely Case 1: Case 1:
ciency Case 1: Mitochon- 1. Exome sequencing erozygous mutations in pathogenic 1st variant reported Parents were asympto-
drial complex 2. Respiratory chain NDUFV1 gene: c.1129G>G/ Case 2: VOUS in literature (Calvo matic carriers
1 deficiency enzyme assay on A;c.1156C>C/T SE et al. Nat Genet. Not tested
OMIM#252010 muscle biopsy of (p.Glu377Lys);(p.Arg386Cys) 2010;42:851–8);
Case 2: Mitochon- complex 1 < 30% Case 2: Homozygous muta- 2nd variant reported
drial complex 1 tions in NDUFA10 gene: in ClinVar
deficiency nuclear c.466G>A;(p.Gly156Ser) Case 2: Novel
type 22 OMIM#
618243
ECHS1D 1 N Exome sequencing Compound heterozygous muta- VOUS Novel Not done
tions (VOUS) in ECHS gene:
1. Missense variation in exon 2;
c.112G>G/C;(p.Ala38Pro)
2. frameshift and prema-
ture truncation exon 2;
c.123_124delAG;(p.Gly-
42GlufsTer3)
Indian Journal of Pediatrics (February 2022) 89(2):184–191
Table 1  (continued)
Category Number Predominant Test which confirmed Genetic variations identified Type of variant Novel/Reported Segregation analysis
presentation the diagnosis variant
Leigh disease 1 N Exome sequencing Homozygous pathogenic Pathogenic Reported (Lee IC, Not done
mutations in SURF 1 gene: et al. Hum Mutat.
c.[833 + 1G>A](5’splice site) 2012;33:1192– 200)
PDH deficiency 1 N Exome sequencing Heterozygous mutation in Likely pathogenic Novel Not done
PDHA1 gene: c.380G>C;
(p.Gly127Ala). Confirmed on
Sanger sequencing
IV. UCD
Citrullinemia 3 E Plasma amino acids In all 3 cases same homozygous Pathogenic/Likely Reported (ClinVar) Case 1 & 2: Both par-
showing elevation variants in ASS1 gene: pathogenic ents were carriers
of citrulline > 1000 c.1168G>A;(p.Gly390Arg) Case 3: Not done
umol/L
Argininemia 1 N Plasma amino acids -
Indian Journal of Pediatrics (February 2022) 89(2):184–191

plasma arginine > 3

times upper limit of
normal
V. Carbohydrate
metabolism defects
Galactosemia 1 E Galactose - 1 Homozygous pathogenic Pathogenic Reported (ClinVar) Not done
phosphate uridyl variants in GALT gene: c.563
transferse (GALT) A>G;(p.Gln188Arg)
enzyme assay
GSD 3 1 O Exome sequencing Homozygous variants in AGL Likely pathogenic Novel. But dif- Not done
gene: c.4544G>T ferent missense
(p.Cys1515Phe) mutation involv-
ing same codon
p.Cys1515Arg has
been reported
FBP1 deficiency 1 E Elevated glycerol,
ketones, and lactic
acid metabolites on
urine organic acids
(GCMS)
UGP2 deficiency 1 DD/S Exome sequencing Homozygous variants in UGP2 VOUS Reported (Per- Parents were carriers
gene: c.34A>G;(p.Met12Val) enthaler E, et al.
Acta Neuropathol.
2020;139:415–42)
187
Table 1  (continued)
188

Category Number Predominant Test which confirmed Genetic variations identified Type of variant Novel/Reported Segregation analysis
presentation the diagnosis variant
VI. Aminoacidopathies
PKU 3 DD Serum amino
acids phenylala-
nine > 120 nmol/ml
with Phe/Tyr > 3
Hyperprolinemia 1 DD Serum amino acids -
proline levels 599
umol/L (normal
- 51–270 umol/L),
urine organic acids
normal, serum
lactate normal
VII. CCD 3 DD/S MR spectroscopy 1. Homozygous vari- Case 1: Likely Case 1 & 2: Novel Not done
showing absent ants in GAMT gene: pathogenic
creatine peak c.265_267ATC;(p.Ile89del) Case 2: pathogenic
2. Homozygous variants in
SLC6A8 gene:c.516 T>A
(p.Cys172Ter)
VIII. Neurotransmitter
deficiency disorder
SSADH deficiency 2 DD Urine organic acids- Both patients had homozy- Pathogenic Novel Patients were brothers
high 4 OH butyric gous 16 base pair inser- (Sanger sequencing
acid tion in ALDH5A1 gene: done)
c.278_279insCGG​GGT​GCG​
AGA​GGCC;(p.Ala100Glyf-
sTer41)
Dopa responsive 1 DD Exome sequencing Homozygous pathogenic Pathogenic Reported (van den Parents were carriers
dystonia variants in TH gene: Heuvel LP, et al.
c.698G>A;(p.Arg233His) Hum Genet.
1998;102:644–6)
IX. FAOD
VLCAD 1 E MS/MS show- Homozygous variants in Likely pathogenic
ing elevated ACDAVL gene: c.1426C>T;(p.
C14 = 11.5uM (Nor- Arg476Ter)
mal: 0.04 – 0.8uM),
C14: 1 = 13.97 uM
(normal: 0.01–0.52
uM), C16:1 = 2.3
(normal 0.02– 0.85
uM) acylcarnitines
Indian Journal of Pediatrics (February 2022) 89(2):184–191
Table 1  (continued)
Category Number Predominant Test which confirmed Genetic variations identified Type of variant Novel/Reported Segregation analysis
presentation the diagnosis variant

CPT-1 deficiency 1 E MS/MS C0 = 210

uM (normal 9–65,
C16 = 0.1 uM (nor-
mal 0.34 – 10.35
uM), C18 = 0.17
uM (normal 0.21
– 2.03 uM); C0/
C16 + C18 = 777
(normal < 30)
X. Vitamins, cofactors
& metals-related
disorders
Biotinidase 1 DD Biotinidase enzyme
Indian Journal of Pediatrics (February 2022) 89(2):184–191

assay
MoCo deficiency 1 E Elevated plasma and Child died before she could be VOUS Reported (Hannah- Both parents were
urine sulphocysteine tested Shmouni F, et al. heterozygous
Mol Genet Metab carriers of same
Rep. 2018;18:11– variant in MOCS2
3) gene:c.*146G>A
MTHFR deficiency 1 DD/S Elevated serum homo- Compound heterozygous for Likely pathogenic Both variants Father variant-
cysteine MTFHR gene: c.1130G>G/A; reported in ClinVar c.1130G>G/A
c.1072C>C/T (Lossos A, et al. Mother variant-
(p.Arg377His); JAMA Neurol. c.1072C>C/T
(p.Arg358Ter) 2014;71:901–4;
Massadeh S, et al.
Front Neurol.
2019;10:411)
Menkes disease 1 E Low serum copper
and serum cerulo-
plasmin

3HMG CoA deficiency 3-hydroxy-3-methylglutaryl CoA lyase deficiency; CCD Cerebral creatine deficiency; CPT-1 Carnitine palmitoyltransferase 1 deficiency; DD Developmental delay; DD/S
Developmental delay/seizures; E Encephalopathy; ECHS1D Mitochondrial short chain enoyl CoA hydratase deficiency; FAOD Fatty acid oxidation defects; FBP1D Fructose-1,6-bisphosphatase
deficiency; GA1 Glutaric acuduria type 1; GD Gaucher disease; GSD3 Glycogenstorage disorder type III; LSD Lysosomal storage disorder; MMA Methylmalonic academia; MoCoD Molybde-
num cofactor deficiency; MPS Mucopolysaccharidosis; MS/MS Tandem mass spectrometry; MTHFR Methylenetetrahydrofolate reductase; N Neuroregression; NPD Niemann–Pick disorder;
O Organomegaly; OA Organic aciduria; PA Propionic academia; PKU Phenylketonuria; SSADH Succincyl semialdehyde dehydrogenase deficiency; UCD Urea cycledisorders; UGP2D UDP-
glucose pyrophosphorylase deficiency; VLCAD Very-long-chain acyl-CoA dehydrogenasedeficiency; VOUS Variant of uncertain significance
189
190
followed by organic acidurias 8 (16%), mitochondrial dis-
orders 5 (10%), urea cycle disorders, carbohydrate metabo-
lism disorders and aminoacidopathies 4 (8% each), fatty
acid oxidation defects and neurotransmitter deficiency
disorders 3 (6% each), and miscellaneous (8%) (Table 1).
The predominant presentations were neurological with
developmental delay/seizures in 19 (38%), acute encepha-
lopathy in 16 (32%), neuroregression in 9 (18%), and orga-
nomegaly in 6 (12%). Symmetrical basal ganglia lesions
on magnetic resonance imaging of the brain were seen
in 17 of the 22 patients in whom it was done. It is useful
for pattern recognition especially in children with neu-
roregression or encephalopathy. In 25 children (50%), a
genetic variation was identified (Table 1).
Acylcarnitine profile in blood and urine organic acids
was diagnostic in 10/16 (62.5%) children with IEM who
presented with acute encephalopathy. Specific enzyme
assay was diagnostic in 5/6 (83.3%) children presenting
with organomegaly. Genetic testing was diagnostic in
55.5% of patients with neuroregression. However, chil-
dren who presented with developmental delay with or
without seizures needed the whole gamut of biochemical,
radiological, and genetic testing to confirm the diagnosis.
Twenty-four children could be medically treated. Overall,
12 were lost to follow-up, 14 died, and 24 were alive at
last follow-up.
Discussion
The spectrum of various IEMs diagnosed in 50 children
from a single center in central India is presented. Of these,
45 were potentially treatable disorders. In the present
series, lysosomal storage disorders were the commonest
large molecule disorder accounting for 26% and organic
acidurias were the commonest small molecule disorder
accounting for 16% of cases, similar to the case series by
Ganesh et al. from South India [4]. The commonest lysoso-
mal storage disorders in the present study were mucopoly-
saccharidosis (6/13), while glycolipid storage disorders
were the commonest in the lysosomal storage disorders
reported by Sheth et al. [8]. Consanguinity was seen in
18% of patients in the present series compared to a much
larger incidence of 65% from South India [4].
The genetic variations detected in half of the patients
are also reported in the present series. In a study from
Spain, children with abnormal results on newborn screen-
ing (acylcarnitines and amino acid levels on dried blood
sample) underwent targeted exome sequencing to look for
inborn errors of metabolism [10]. The metabolic disorder
suspected was confirmed in 83/141 (59%) of these patients.
Carrier status was confirmed in a further 39 cases. This
Indian Journal of Pediatrics (February 2022) 89(2):184–191
highlights the growing role of exome sequencing in the
diagnosis of IEMs and a need to collate Indian data.
Conclusions
In a resource-limited setting, the present analysis suggests
that it would be useful to first look at acylcarnitine profiles
and urine organic acids in children with acute encephalopa-
thy; specific enzyme assay should be carried out in patients
presenting with organomegaly and exome sequencing in
children with neuroregression as well as when metabolic
tests and enzyme assays are nondiagnostic, and in genetically
heterogeneous phenotypes such as developmental delay, sei-
zure, and movement disorders. However, biochemical tests
remain important as they can help to reclassify genetic vari-
ants of uncertain significance. Since this is a retrospective
study from a single center with its inherent referral bias, it is
not an accurate reflection of the actual prevalence of various
inborn errors of metabolism but identifies some common
categories of IEMs seen in central India.
Acknowledgements The authors thank the patients and residents of
the Department of Pediatrics, Choithram Hospital & Research Center,
Indore.
Authors' Contributions GRP contributed to the planning, data collec-
tion, analysis and writing of the manuscript; AW contributed to data
collection; SPJ contributed to data collection and critical appraisal.
GRP will act as the guarantor for this paper.
Declarations
Conflict of Interest None.
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