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

In spite of the efforts and interventions by the Government of Pakistan and The World Health Organization, the neonatal mortality in Pakistan has declined by only 0.9% as compared to the global average decline of 2.1% between 2000 and 2010. This has resulted in failure to achieve the global Millennium Development Goal 4. Hypoxic-ischaemic encephalopathy, still birth, sepsis, pneumonia, diarrhoea and birth defects are commonly attributed as leading causes of neonatal mortality in Pakistan. Inherited metabolic disorders often present at the time of birth or the first few days of life. The clinical presentation of the inherited metabolic disorders including hypotonia, seizure and lactic acidosis overlap with clinical features of hypoxic-ischaemic encephalopathy and sepsis. Thus, these disorders are often either missed or wrongly diagnosed as hypoxicischaemic encephalopathy or sepsis unless the physicians actively investigate for the underlying inherited metabolic disorders. We present 4 neonates who had received the diagnosis of hypoxic-ischaemic encephalopathy and eventually were diagnosed to have various inherited metabolic disorders. Neonates with sepsis and hypoxic-ischaemic encephalopathy-like clinical presentation should be evaluated for inherited metabolic disorders.

Carbamoylphosphate synthetase 1 (CPS1) deficiency: clinical, biochemical, and molecular characterization in Malaysian patients.

UNLABELLED: Carbamoyl phosphate synthetase 1 (CPS1) deficiency is a rare autosomal recessive disorder of ureagenesis presenting as life-threatening hyperammonemia. In this study, we present the main clinical features and biochemical and molecular data of six Malaysian patients with CPS1 deficiency. All the patients have neonatal-onset symptoms, initially diagnosed as infections before hyperammonemia was recognized. They have typical biochemical findings of hyperglutaminemia, hypocitrullinemia, and low to normal urinary excretion of orotate. One neonate succumbed to the first hyperammonemic decompensation. Five neonatal survivors received long-term treatment consisting of dietary protein restriction and ammonia-scavenging drugs. They have delayed neurocognitive development of varying severity. Genetic analysis revealed eight mutations in CPS1 gene, five of which were not previously reported. Five mutations were missense changes while another three were predicted to create premature stop codons. In silico analyses showed that these new mutations affected different CPS1 enzyme domains and were predicted to interrupt interactions at enzyme active sites, disturb local enzyme conformation, and destabilize assembly of intact enzyme complex. CONCLUSION: All mutations are private except one mutation; p.Ile1254Phe was found in three unrelated families. Identification of a recurrent p.Ile1254Phe mutation suggests the presence of a common and unique mutation in our population. Our study also expands the mutational spectrum of the CPS1 gene.

Pilot study of newborn screening of inborn error of metabolism using tandem mass spectrometry in Malaysia: outcome and challenges.

BACKGROUND: The aim of this study was to determine the feasibility of performing newborn screening (NBS) of inborn errors of metabolism (IEMs) using tandem mass spectrometry (TMS) and the impact on its detection rate in Malaysia. METHODS: During the study period between June 2006 and December 2008, 30,247 newborns from 11 major public hospitals in Malaysia were screened for 27 inborn errors of amino acid, organic acid and fatty acid metabolism by TMS. Dried blood spot (DBS) samples were collected between 24 h and 7 days with parental consent. Samples with abnormal results were repeated and the babies were recalled to confirm the diagnosis with follow-up testing. RESULTS: Cut-off values for amino acids and acylcarnitines were established. Eight newborns were confirmed to have IEM: two newborns with Maple syrup urine disease (MSUD), two with methylmalonic aciduria (MMA) one with ethylmalonic aciduria, two with argininosuccinic aciduria and one with isovaleric aciduria. Diagnosis was missed in two newborns. The detection rate of IEMs in this study was one in 2916 newborns. The sensitivity and specificity of TMS were 80% and 99%, respectively. CONCLUSIONS: IEMs are common in Malaysia. NBS of IEMs by TMS is a valuable preventive strategy by enabling the diagnosis and early treatment of IEM before the onset of symptoms aiming at prevention of mental retardation and physical handicap. A number of shortcomings warrant further solution so that in near future NBS for IEMs will become a standard of care for all babies in Malaysia in tandem with the developed world.

Identification of a novel homozygous mutation (S144I) in a Malay patient with maple syrup urine disease.

Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder of branched-chain amino acid metabolism caused by the defective function of branched-chain α-ketoacid dehydrogenase complex (BCKDH). It is characterised by increased plasma leucine, isoleucine, and valine levels, and mutations can be detected in any one of the BCKDHA, BCKDHB, and DBT genes. In this study, we describe the molecular basis of a novel mutation found in one MSUD Malay patient from consanguineous parents. A homozygous mutation has been detected in this patient whose both parents carried a heterozygous mutation at DNA coding region c.431G>T in exon 4, which resulted in a substitution of serine to isoleucine at codon 144 (p.S144I). In silico analysis predicted S144I to be potentially damaging. The mutation was located on the alpha helical region of the BCKDHA protein, and it is predicted to affect the stability of protein due to the loss of various polar interactions between local secondary structures. Homology analysis revealed that this mutation occurred in a highly conserved region (100%). This result indicates that S144I mutation is likely pathogenic and may contribute to the classic form of MSUD in this patient.