Biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia

Abstract

ObjectiveNonketotic hyperglycinemia is a neurometabolic disorder characterized by intellectual disability, seizures, and spasticity. Patients with attenuated nonketotic hyperglycinemia make variable developmental progress. Predictive factors have not been systematically assessed.MethodsWe reviewed 124 patients stratified by developmental outcome for biochemical and molecular predictive factors. Missense mutations were expressed to quantify residual activity using a new assay.ResultsPatients with severe nonketotic hyperglycinemia required multiple anticonvulsants, whereas patients with developmental quotient (DQ) > 30 did not require anticonvulsants. Brain malformations occurred mainly in patients with severe nonketotic hyperglycinemia (71%) but rarely in patients with attenuated nonketotic hyperglycinemia (7.5%). Neonatal presentation did not correlate with outcome, but age at onset ≥ 4 months was associated with attenuated nonketotic hyperglycinemia. Cerebrospinal fluid (CSF) glycine levels and CSF:plasma glycine ratio correlated inversely with DQ; CSF glycine > 230 μM indicated severe outcome and CSF:plasma glycine ratio ≤ 0.08 predicted attenuated outcome. The glycine index correlated strongly with outcome. Molecular analysis identified 99% of mutant alleles, including 96 novel mutations. Mutations near the active cleft of the P‐protein maintained stable protein levels. Presence of 1 mutation with residual activity was necessary but not sufficient for attenuated outcome; 2 such mutations conferred best outcome. Divergent outcomes for the same genotype indicate a contribution of other genetic or nongenetic factors.InterpretationAccurate prediction of outcome is possible in most patients. A combination of 4 factors available neonatally predicted 78% of severe and 49% of attenuated patients, and a score based on mutation severity predicted outcome with 70% sensitivity and 97% specificity. Ann Neurol 2015;78:606–618

Nonketotic hyperglycinemia: Functional assessment of missense variants inGLDCto understand phenotypes of the disease

“…Our results strongly agree with a previous study that the total loss of GCS P‐protein activity causes a classic severe NKH phenotype, whereas milder phenotypes correspond to variants maintaining reduced but present activities, with the mildest phenotype observed in patients with both alleles with mutations that confer residual activity such as P23 in this study (Swanson et al., ). Data from Western blot and protein structure analysis suggest that for an important number of mutants in our series, the loss‐of‐function character could correlate with a decreased stability, thus identifying in many patients classic NKH as a conformational disease.…”

“…Relative to the wild type, GCS P‐protein activities were less than 1% in homogenates from cells expressing p.Thr146Lys, p.Leu173Pro, p.His580Tyr, p.Pro581Arg, pAla624Asp, p.Gly763Asp, p.Gly768Glu, or p.Gly994Arg, and retained measurable activities between 1% and 10% of wild type with the p.Pro267Ala, p.Arg362Cys, p.Arg373Trp, p.Leu548Pro, p.Asp866His, and p.Val905Gly variants. Homogenates from cells transfected with the variants p.Met1Ile, p.Lys376Glu, p.Arg461Trp, p.Arg790Trp, and p.Ile933Thr rendered GCS P‐protein glycine exchange activities ranging from 12% to 50% and were identified as very mild, similar to previously published data (Swanson et al., ). Due to the nature of this functional assay, far from the natural biological environment of patient's cells, it is possible that the effect of certain variants could be missed; this could be the case for p.Met1Ile, which affects the initiation start codon.…”

“…This compendium of new 19 GLDC missense mutations analyzed in the context of a genotype–phenotype correlation will be helpful for clinicians when evaluating the benefit of specific interventions during the neonatal period. Patients who have at least one mutation that allows for residual enzyme activity, many of them described here, have the potential to develop attenuated NKH, and data from a sibling study indicate that early treatment improves outcome (Bjoraker et al., ; Swanson et al., ). This extended study of expressed mutations helps clinicians identify more patients with residual activity that best benefit from early treatment.…”

“…Based on a combination of CSF glycine levels, age at onset, and clinical outcome, we distinguished between attenuated NKH and severe NKH with poor developmental outcome or neonatal fatality in combination with high levels of glycine in CSF and neonatal onset (Swanson et al., ). In this study, 16 out of the 26 patients had severe NKH with an initial onset of hypotonia, apnea, myoclonic jerks, and deceased in the neonatal or early infancy period with a severe outcome.…”

Nonketotic hyperglycinemia: novel mutation in the aminomethyl transferase gene. Case report

“…The outcome is poor, some patients dying during the newborn period; survivors usually exhibit severe mental retardation and intractable seizures. Swanson et al 9 published biochemical and molecular predictors for prognosis in nonketotic hyperglycinemia recently. In this study of 124 patients, there were 26 patients (21%) who died in the neonatal or early infantile period.…”