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Inherited metabolic disorders presenting as hypoxic ischaemic encephalopathy: A case series of patients presenting at a tertiary care hospital in Pakistan.

Byline: Maya Zahid, Aysha Habib Khan, Zabedah Md Yunus, Bee Chin Chen, Beat Steinmann, Haberle Johannes and Bushra Afroze

Keywords: Hypoxic-ischemic encephalopathy, Molybdenum cofactor deficiency, Pyruvate carboxylase deficiency, Zellweger syndrome, Non-ketotichyperglycinaemia.

Introduction

Hypoxic Ischaemic Encephalopathy (HIE) remains a problem of great concern worldwide especially in developing countries. HIE occurs in neonates who display signs of perinatal distress, entail resuscitation at birth, and develop neurological symptoms within 24 hours after delivery.1 At delivery, HIE neonates may have low APGAR scores with associated bradycardia, poor respiratory effort, hypotonia, decreased alertness, weak or absent cry, and abnormal skin colour. The presence of metabolic acidosis in cord blood with pH <7 is higly suggestive of HIE. Currently, perinatal asphyxia associated with moderate to severe HIE affects between 1-2/1,000 live births in the developed countries and between 10-20/1,000 live births in the developing countries. HIE is reported to contribute to 1/3 of the neonatal mortality.2 Inherited Metabolic Disorders (IMDs) are a heterogeneous group of disorders, which cumulatively affect approximately 1 in 800 neonates.3 A number of IMD present with HIE-like symptoms.

Thus, IMD should be included in the differential diagnosis of neonates who present with nonspecific features suggestive of HIE. We report four neonates who had HIE-like presentation and were diagnosed to have IMD.

Case Report

Patient 1

A boy who was born at term after an uneventful pregnancy was noted to have poor suckling, excessive crying and jitteriness on day 1 of life (D1OL). He developed seizures on the D2OLand required ventilator support for 5 days. He was discharged on D16OL on three anti-convulsants with the diagnosis of HIE.

At 2.5 month of age he was seen at our metabolic clinic at Aga Khan University Hospital in 2016 for intractable epilepsy and absence of social smile, eye contact and face regard for the mother. On examination, his weight was 4.7kg (25th percentile), length 59.5cm (75th percentile) and Fronto-Occipital Circumference (OFC) 38cm (10th percentile). He was noted to have hypotonia and depressed reflexes. As part of screen for metabolic disorders, biochemical labs were done, which showed normal plasma lactate and ammonia. Mildly elevated methionine and taurine, markedly low cysteine levels on plasma amino acid analysis (PAA) were noted along with significant hypouricaemia. Brain MRI showed cystic encephalomalacia. Based on the clinical features, hypouricaemia and hypocystinaemia prompted the differential diagnosis of Molybdenum cofactor deficiency (MAdegCD), which was confirmed on the classical pattern of urine purine analysis (raised xanthine and hypoxanthine) with elevated urinary sulphocysteine.

Table-1: History of the 4 patients with IMD presenting as HIE.

Patient###1###2###3###4

Gestational age (weeks)###38###37###36 + 3 days###37

Prenatal complications###None###Hydrocephalus on ultrasound scans###IUGR###None

Parental consanguinity###First-cousins###First-cousins###First-cousins###First-cousins

History of Sibling with###Twins, one had hypotonia and###One sibling died with###Death of a sibling on D7OL###One sibling

similar presentation###seizures, died D2OL and the###similar presentation but###with "Brain anomaly"###died of a similar

###other had delayed milestones###no antenatal###and birth###presentation

###and seizures, died at 6 months of age###diagnosis###asphyxia###on D7OL

Table-2: Clinical features of the 4 patients with IMD presenting as HIE.

Patient###1###2###3###4

Birth weight(kg)###2.8 (10th percentile)###2.8 (5th percentile)###1.8 (97th percentile)###30(<3rd percentile)###34 (50th percentile)

APGAR Score###NA###8 at 1 min, 9 at 5 min###NA###8 at 1 min, 9 at 5 min

Clinical Features###+ Hypotonia###+ Hypotonia###+ Hypotonia###+ Hypotonia

###+ Jitteriness on D1OL and seizures on D2OL###+Grunting soon after birth###+ Poor suckling###+ Poor suckling

Current status (Alive/Dead)###Alive- 1 year old###Patient expired on 4th day of life###Patient expired at###Patient expired at the

###the age of 4 months###age of 1.5 months

Table-3: Biochemical and molecular findings of the 4 patients with IMD presenting as HIE.

Patient###1###2###3###4

Relevant Biochemical and###Plasma L.A:2.0###Plasma L.A:17.9###Plasma L.A: 2.1###Plasma L.A:7.7

Radiological Labs###(N:0.5-2.2mmol/L)###(N: 0.5-2.2mmol/L)###(N: 0.5-2.2 mmol/l). Plasma NH4:184###(N: 0.5-2.2mmol/L)

###Plasma NH4:49###Plasma NH4:842###(N: <100 mol/L)###Plasma NH4:68

###(N:<100 mol/L)###(N:<100 mol/L)###C24:0 1.5282###(<100 mol/L).

###Plasma Methionine:79###Plasma citrulline:150###(N: <1.529)###Plasma Glycine:1591

###(N:5-32 mol/L)###(N: 5-33mol/L)###C26:0 0.5101###(N: 101-317 mol/L)

###Plasma Taurine:179###Plasma lysine:443###(N: <0.085)###CSF Glycine:387.6

###(N:11-93mol/L)###(N: 67-291mol/L)###Babygram: Punctate discrete###(N: 3-8.3 mol/L)

###calcification in the patella. Fig. 1

###Plasma Cystine: 6###Plasma Glutamine:173###Plasma fatty acids:###CSF Glycine: Plasma Glycine ratio: 0.24

###(N:33-57mol/L)###(N: 198-886mol/L)###(N: <0.02) Electroencephalogram:

###Burst suppression pattern

###Plasma Uric acid: <0.5

###(N: 2-5 mg/dl).

###Urinary Sulphocysteine: 216

###(N:T###ND

###in exon 22 in PC gene^.###(p.Arg959*)in the PEX1 gene^.

Diagnosis###Molybdenum cofactor deficiency###Pyruvate carboxylase deficiency###Zellweger syndrome###Non-ketotichyperglycinemia

Table-4: Brain MRI findings of the 4 patients with IMD presenting as HIE.

Patient###1###2###3###4

MRI Brain Findings###Cystic encephalomalacia.###Bilateral periventricular and subependymal###Polymicrogyria in the frontal lobes,###Normal

###Fig 2a.###cysts in the caudothalamic groove and dilated###cavumseptumpallucidum and mild

###lateral ventricles. Fig 2b.###hypoplasia of the inferior vermis. Fig 2c.

###NMRS: Large peak of 2 hydroxy butyric###NMRS: marked excretion of lipids

###acid and small peaks of acetoacetic

###acid and pyruvic acid. Fig 2 b.

Diagnosis###Molybdenum cofactor deficiency###Pyruvate carboxylase deficiency###Zellweger syndrome###Non-ketotichyperglycinemia

Patient 2

A girl was born at term by Lower Segment Caesarean Section (LSCS), due to increased OFC at Aga Khan University Hospital in 2015. Examination revealed open and flat anterior fontanelle, depressed neonatal reflexes and unremarkable systemic examination. The baby was shifted to the NICU after few hours due to grunting, tachypnea and hypotonia. The patient was investigated and managed along the lines of apparent HIE.HIE biochemical markers including serum creatine phosphokinase (CPK), lactate dehydrogenase (LDH), creatinine were raised. Other laboratory workup revealed lactic acidaemia and hyperammonaemia. Urine organic acid (UOA) analysis showed ketosis. PAA revealed high levels of citrulline and lysine and decreasedglutamine levels.

Brain MRI revealed bilateral periventricular cysts and subependymal cysts in the caudothalamic groove along with dilated lateral ventricles. Lactic acidosis and PAA along with the MRI findings prompted the differential diagnosis of pyruvate carboxylase deficiency (PCD), which was confirmed by PC gene sequencing.

Patient 3

A boy was born at term by LSCS, due to intrauterine growth retardation (IUGR). He had poor suckling and hypotonia and was discharged on D9OL with the diagnosis of HIE. He presented at our metabolic clinic on D12OL at Aga Khan University Hospital in 2016 with complaints of poor feeding from birth and generalized hypotonia. Examination of the patient revealed a tower-like skull with large, open anterior and posterior fontanelles. There was severe hypotonia and hypo-reflexes. Based on the clinical features suggestive of Zellweger spectrum-disorder (ZSD), baby-gram was done, which showed patellar calcification. Brain MRI revealed polymicrogyria in the frontal lobes, cavumseptumpallucidum and mild hypoplasia of cerebral vermis. For the biochemical confirmation of ZSD, very long chain fatty acids (VLCFA) were done, which were elevated. ZSD was confirmed by PEX1 gene sequencing.

Patient 4

A girl was born at term by LSCS, due to decreased foetal movements. The newborn developed decreased activity, poor suckling and hypotonia on D2OL progressing to respiratory distress on D5OL requiring ventilator support and was shifted to our hospital with the diagnosis of HIE. HIE biochemical markers were raised. On arrival at Aga Khan University Hospital in 2016, the baby was noted to have severe hypotonia, hyporeflexia and depressed neonatal reflexes. Electroencephalogram showed burst suppression pattern. Brain MRI including corpus callosum was normal. Hyperglycinaemia and raised CSF glycine: Plasma glycine ratio strongly supported the diagnosis of non-ketotic hyperglycinaemia (NKH). The family declined molecular confirmation of the NKH due to financial constraints.

Discussion

IMD may present at or soon after birth with dysmorphic features, seizures and severe hypotonia. Neonates presenting with neurological abnormalities at or soon after birth, particularly the ones with persistent lactic acidosis and early-onset fits, are often misdiagnosed as HIE. More than 800 IMDs are known. A number of IMD present in the early neonatal age with non-specific symptoms of sepsis-like illness or HIE-presentation.4 In local setting, neonates with HIE are rarely investigated for an underlying IMD. Investigations should include analysis of plasma ammonia, plasma lactate, plasma uric acid, blood and CSF lactate, paired plasma and CSF aminoacids, plasma very-long-chain fatty acids, urine ketone bodies and organic acids, urine sulphite, urinary sulphocysteine, and urine purines and pyrimidines.5 Martinelloet al published a practical diagnostic algorithm for the evaluation of patients in whom the diagnosis of HIE is not confirmed.6

The essence of this practical algorithm in this paper is that all newborns with HIE should be investigated for IMD, which is especially applied in our local context as the most new-borns who receive the diagnosis of HIE, the critical parameter of metabolic acidosis with pH<7.0 in cord blood and APGAR score information at birth is missing. Moreover, differentiation of true HIE and other pathologies like an underlying IMD or other genetic condition like neuromuscular disorder causing secondary HIE, is not possible based on the parameters like metabolic acidosis with pH <7.0 in cord blood and poor APGAR score. Pattern of brain injury on brain MRI due to HIE depends on the gestational age, severity and duration of HIE. Preterm neonates suffer periventricular white matter injury, term neonates sustain damage primarily in the cortex and underlying subcortical and periventricular white matter.

Severe HIE may show hyperintense signal in the thalamus and putamen (with relative sparing of the anterior putamen). Brain MRI in many IMDs have disease specific pattern, which if promptly recognized can lead to an accurate diagnosis.7

MAdegCD, PCD, ZSD and NKH are few IMDs, which are known to present as HIE and often are missed if not investigated properly. All four patients had initially received diagnosis of HIE, which eventually turned to be various IMD. Presence of parental consanguinity, family history of intellectual disability, cerebral palsy, seizure, sudden infant deaths, neonatal or early infancy death with symptoms suggestive of an IMD, history of non-immune hydropsfoetalis in previous pregnancy are some pointers, which should alert the physicians for a possible IMD in neonates presenting as HIE. However, absence of these parameter cannot exclude IMD as the primary cause in neonates presenting as HIE. The critical message is that all neonates with HIE needs a diagnostic evaluation for IMD.

The Task Force on Neonatal Encephalopathy published guidelines in 2014, according to which "If a comprehensive etiologic evaluation is not possible, the term hypoxic-ischaemic encephalopathy should best be replaced by neonatal encephalopathy because neither hypoxia nor ischaemia can be assumed to have been the unique initiating causal mechanism".8 Appropriate evaluation of HIE provides the family a chance of a correct diagnosis, proper genetic counseling and future reproductive options.

Disclaimer: None to declare.

Conflict of Interest: None to declare.

Funding Sources: None to declare.

References

1. Mercuri E, Guzzetta A, Haataja L, Cowan F, Rutherford M, Counsell S. Neonatal neurological examination in infants with hypoxic ischaemic encephalopathy: correlation with MRI findings. Neuropediatrics. 1999; 30:83-9.

2. Perez JM, Golombek SG, Sola A. Clinical hypoxic-ischemic encephalopathy score of the Iberoamerican Society of Neonatology (Siben): A new proposal for diagnosis and management. Rev Assoc Med Bras (1992). 2017; 63:64-9.

3. Mak CM, Lee HC, Chan AY, Lam CW. Inborn errors of metabolism and expanded newborn screening: review and update. Crit Rev Clin Lab Sci. 2013; 50:142-62.

4. Patay Z. MR imaging workup of inborn errors of metabolism of early postnatal onset. MagnResonImagingClin N Am. 2011; 19:733-59.

5. Leonard JV, Morris AA. Diagnosis and early management of inborn errors of metabolism presenting around the time of birth.Acta Paediatr. 2006; 95:6-14.

6. Martinello K, Hart AR, Yap S, Mitra S, Robertson NJ. Management and investigation of neonatal encephalopathy: 2017 update.Arch Dis Child FetalNeonatal Ed.2017;102:F346-58.

7. Enns GM. Inborn errors of metabolism masquerading as hypoxic-ischemic encephalopathy.NeoReviews. 2005;6:e549-58.

8. Schendel D. Executive summary: neonatal encephalopathy and neurologic outcome, Report of the American College of Obstetricians and Gynecologists' task force on neonatal encephalopathy. ObstetGyneco. 2014; 123:896-901.
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Publication:Journal of Pakistan Medical Association
Article Type:Report
Geographic Code:9PAKI
Date:Mar 31, 2019
Words:2277
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