Novel compound heterozygous LIAS mutations cause glycine encephalopathy.

Glycine encephalopathy (GCE) is a rare autosomal recessive disorder caused by defects in the glycine cleavage complex. Here we report a patient with GCE and elevated level of glycine in both the serum and the cerebrospinal fluid. Trio-based whole-exome sequencing identified novel compound heterozygous mutations (c.738-2A>G and c.929T>C (p.Met310Thr)) in LIAS. To date, three homozygous mutations have been reported in LIAS. All previously reported GCE patients also show elevated level of serum glycine. Our data further supports LIAS mutations as a genetic cause for GCE.

Nonketotic hyperglycinemia: a cause of encephalopathy in children.

Nonketotic hyperglycinemia is a rare metabolic disorder with severe, frequently fatal, neurologic manifestations. Reliable and accurate diagnosis depends on careful interpretation of laboratory findings. The clinical suspicion should lead to determination of glycine in plasma and cerebrospinal fluid. Amino acid analysis presents diagnostic values for classic nonketotic hyperglycinemia, but it also should be performed in suspected cases of atypical nonketotic hyperglycinemia and in children with seizures, failure to thrive, behavior problems, and uncoordinated movements. Clinical assessment should be reinforced by demonstration of elevated cerebrospinal fluid-to-plasma glycine ratio. Confirmatory diagnosis requires enzymatic and genetic investigation of glycine cleavage system. An early diagnosis, though not affecting clinical outcome, allows proper genetic counseling, with the possibility of prenatal diagnosis. We report 3 cases of nonketotic hyperglycinemia, 2 typical neonatal and 1 atypical, diagnosed in Pediatric Hospital of Coimbra, Portugal, and investigated at Laboratory of Biochemical Genetics in 2004 to 2010 (incidence 1:47 455; prevalence 1:782 951).

Pitfalls in measuring cerebrospinal fluid glycine levels in infants with encephalopathy.

In encephalopathic infants, cerebrospinal fluid hyperglycinemia and elevated cerebrospinal fluid to plasma glycine ratio are considered pathognomonic of nonketotic hyperglycinemia. To evaluate the significance of cerebrospinal fluid hyperglycinemia and elevated cerebrospinal fluid to plasma glycine ratio in acutely encephalopathic infants, a retrospective chart review of all cases of isolated elevation of cerebrospinal fluid glycine levels at Arkansas Children's Hospital from January 1995 to December 2000 was performed. Twenty-two patients (14 males) were included. The most common diagnosis was hypoxic ischemic encephalopathy (n = 8). Nine patients had elevated cerebrospinal fluid to plasma glycine ratio, which was transient in 7 patients. This study shows that elevated cerebrospinal fluid to plasma glycine ratio can be encountered in a variety of clinical conditions. The significance of this observation in light of the poor prognosis of nonketotic hyperglycinemia and the possible role of glycine in the mechanism of ischemic neuronal injury is addressed.

Nonketotic hyperglycinemia: proposal of a diagnostic and treatment strategy.

Early myoclonic encephalopathy presents neonatally with fragmented myoclonus and a suppression-burst electroencephalography pattern. We describe a newborn boy with early myoclonic encephalopathy caused by nonketotic hyperglycinemia. He presented with severe hypotonia, progressive apneic episodes, and erratic myoclonus. Screening of deletions in GLDC, using the multiplex ligation-dependent probe amplification method, and a (13)C breath test confirmed the diagnosis of nonketotic hyperglycinemia. Treatment with the N-methyl-d-aspartate receptor antagonist ketamine exerted dramatic suppressive effects on his seizures, and ameliorated his clinical status.

Intracerebral blood and MRS in neonatal nonketotic hyperglycinemia.

Nonketotic hyperglycinemia is an inborn error of glycine metabolism leading to the accumulation of glycine in the brain. The neonatal form presents in the first days after birth with encephalopathy, seizures. and characteristic "hiccups." Rapid progression can lead to intractable seizures, coma, and respiratory failure. The outcome is invariably poor, and many die before age 1 year. The diagnosis of nonketotic hyperglycinemia is traditionally based on the finding of a raised cerebrospinal fluid-to-plasma-glycine ratio. An elevated glycine peak, using long echo time proton magnetic resonance spectroscopy, is also specific to nonketotic hyperglycinemia. The presence of blood in a cerebrospinal fluid sample is known to render the glycine level uninterpretable. However, there have been no reports of intracerebral blood confounding the cerebral glycine detected on long echo time proton magnetic resonance spectroscopy. We report on an infant who presented with neonatal encephalopathy and imaging findings consistent with hypoxic-ischemic encephalopathy, as well as intracerebral hemorrhage and an abnormal glycine peak on spectroscopy. The source of the abnormal glycine on long echo time proton magnetic resonance spectroscopy was intracerebral blood, highlighting an important confounder in the interpretation of long echo time proton magnetic resonance spectroscopy in suspected nonketotic hyperglycinemia.

Treatment from birth of nonketotic hyperglycinemia due to a novel GLDC mutation.

OBJECTIVE: To determine whether the devastating outcome of neonatal-onset glycine encephalopathy (NKH) could be improved by instituting treatment immediately at birth rather than after symptoms are already well established. METHODS: A newborn with NKH diagnosed prenatally following the neonatal death of a previous affected sibling was treated from birth with oral sodium benzoate (250 mg/kg/day) and the NMDA receptor antagonist ketamine (15 mg/kg/day) immediately after sampling cord blood and cerebrospinal fluid (CSF) for glycine determination. Glycine cleavage system (CGS) activity was determined in placental tissue. Mutation analysis was performed by sequencing all GLDC, GCSH and AMT exons. RESULTS: CSF glycine (99 micromol/L, reference 3.8-8.0) was already markedly elevated at birth. GCS activity in placental tissue was severely reduced (2.6% of controls). A novel homozygous GLDC c.482A-->G(Y161C) missense mutation was identified. Neonatal hypotonia and apnea did not occur but the long-term outcome was poor, with intractable seizures and severe psychomotor retardation. This contrasts with the favorable outcome with early treatment in variant NKH with mild GCS deficiency (Ann Neuol 2004;56:139-143). INTERPRETATION: Prospective treatment with this regimen can favorably modify the early neonatal course of severe NKH but does not prevent the poor long-term outcome, suggesting glycine-induced prenatal injury and/or ongoing postnatal damage.

Magnetic resonance imaging in neonatal nonketotic hyperglycinemia.

This report presents two neonates with nonketotic hyperglycinemia in whom conventional magnetic resonance imaging revealed structural cerebral abnormalities, diffusion-weighted imaging indicated abnormalities of myelinated white matter, and magnetic resonance spectroscopy provided biochemical evidence of elevated cerebral glycine levels. The early use of combined magnetic resonance modalities in these severely affected infants helped in prognostication and clinical management.

Four cases of neonatal non-ketotic hyperglycinaemia.

Non-ketotic hyperglycinaemia is an autosomal recessive disorder of glycine metabolism caused by a defect in the glycine cleavage system. Affected neonates present with lethargy, feeding difficulty, hypotonia, apnoea, poorly controlled convulsions and coma. Four cases are reported, three of whom died in the neonatal period. The fourth case was treated with dextromethorphan and sodium benzoate. He survived with neurodevelopmental delay but is now almost seizure-free.