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Original Article

Experiences during newborn screening for glutaric aciduria type 1: Diagnosis, treatment, genotype, phenotype, and outcomes

Tsai, Fang-Chiha; Lee, Han-Juib,c; Wang, An-Guord,e; Hsieh, Shu-Chena; Lu, Yung-Hsiua,f; Lee, Ming-Cheg,h; Pai, Ju-Shana; Chu, Tzu-Hunga; Yang, Chia-Fenga,c,i; Hsu, Ting-Ronga,f; Lai, Chih-Jouj; Tsai, Ming-Tzua; Ho, Ping-Hsuna; Lin, Min-Chiehk; Cheng, Ling-Yeej; Chuang, Ya-Chinj; Niu, Dau-Minga,f,*

Author Information
Journal of the Chinese Medical Association: April 2017 - Volume 80 - Issue 4 - p 253-261
doi: 10.1016/j.jcma.2016.07.006

    Abstract

    1. Introduction

    Glutaric aciduria type 1 (GA-1) is an autosomal recessive organic aciduria caused by glutaryl-CoA dehydrogenase (GCDH) deficiency.1 This results in impaired metabolism of L-lysine, L-hydroxylysine and L-tryptophan, leading to an accumulation of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA), glutaconic acid, and glutarylcarnitine (C5DC). GA and 3-OH-GA are putatively neurotoxic.2 More than 200 disease-causing mutations in the GCDH gene (chromosome 19p13.2) have been identified.3,4

    Without treatment, around 90% of patients will suffer from an acute encephalopathic crisis between 3 to 36 months of age. The crisis is often precipitated by infection, vaccination, and/or surgery.5 The neurological sequela is striatal injury, which manifests as dystonia and axial hypotonia.6,7 Encephalopathic crises are associated with high morbidity and mortality.5,8 Some patients develop neurological impairment but have no documented encephalopathic crisis; these are classified as insidious-onset.9,10 Macrocephaly is a common presentation during infancy, but is frequently overlooked. Due to absence of characteristic features before an encephalopathic crisis, early diagnosis is difficult. Consequently, newborn screening for GA-1 has been established. Treatment for GA-1 consists of a low lysine diet, carnitine, and high-energy intake during illness.11 Early diagnosis and rigorous treatment have lowered the frequency of encephalopathic crises.5,7,12 Despite early treatment, neurodevelopmental deficits are commonly detected.13

    In Taiwan, newborn screening for GA-I started in 2001 and has been mandated since 2006; however there have been only a few small-scale reports describing GA-1 in Taiwan.14–17 We describe our experience with Taiwan's largest newborn screening population. This included eleven patients diagnosed with GA-1 (nine by newborn screening and two clinically). We have compared their outcomes.

    2. Methods

    2.1. Newborn screening for GA-1

    Between January 2001 and October 2015, 1,490,636 newborns were screened for GA-1 using tandem mass spectrometry at the Taipei Institute of Pathology (TIP) and the Chinese Foundation of Health (CFH), two national newborn screening centers in Taiwan. Glutarylcarnitine (C5DC) concentration was measured. The borderline cut-off value for C5DC was ≥0.4 μM at the TIP, and ≥0.3 μM at the CFH. The positive cut-off values were >0.8 μM at the TIP, and ≥0.6 μM at the CFH. If the screened value was equal to or greater than the positive cut-off value, the newborn was referred for confirmatory diagnosis immediately. If the screening value was between the borderline cut-off value and the positive cut-off value, a second sampling was performed. If the second value was still abnormal, the newborn was referred for confirmatory diagnosis.

    2.2. Confirmatory diagnosis

    Urine organic acid and plasma amino acid analyses were performed. It has been reported that missed cases of GA-1 are possible due to secondary carnitine depletion.18,19 To avoid false-negative C5DC results on repeated samples, we developed the carnitine loading test.20 Carnitine (100 mg/kg/day) was given orally for 3 days. Dry blood spots were obtained before and 2 hours after the test. Mutation analysis was performed when urinary GA and 3-OH-GA were found or when the C5DC concentration was more than 0.3 μM after the carnitine loading test.

    2.3. Patient management

    Treatment was started immediately after diagnosis. The maintenance treatment consisted of carnitine and a low lysine diet supplemented with GA-1 special formula (Glutarex-1, Abbott Nutrition, Ltd., Columbus, Ohio, USA or GA1 Anamix Infant, SHS International, Ltd., Liverpool, Merseyside, UK). Recent studies demonstrated that arginine supplementation lowered cerebral GA and 3-OH-GA concentrations in a mouse model and could improve the GA-1 patient outcome, therefore arginine has been prescribed since 2012.21–23 Parents were instructed regarding emergency treatment. During intercurrent illness, catabolism needs to be prevented promptly by providing a high-energy intake. Patients were seen at our clinic every three months. Non-contrast magnetic resonance imaging (MRI) including T1-weighted and T2-weighted images, diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC) maps were obtained at diagnosis and when new neurological symptoms presented.

    Standard deviation scores for weight and height were calculated using the World Health Organization growth charts. Neurological outcomes were evaluated using cognitive functioning and disability scores as proposed by Kyllerman et al.8 All children with GA-I who had undergone follow-up in our hospital since October 2002 were included. This study was approved by the institutional review board of the Taipei Veterans General Hospital, Taipei, Taiwan, ROC.

    2.4. Statistics

    Mann-Whitney U test, Kruskal-Wallis test, and Dunn's multiple comparison test were used. Statistical significance was identified when p < 0.05. Calculations were performed using GraphPad Prism, Version 6.0c (GraphPad Software, CA, USA).

    3. Results

    3.1. Newborn screening

    Among the 1,490,636 newborns screened, 14 newborns were confirmed to have GA-1. The incidence of GA-1 in this Taiwanese population was 1 in 106,474. Eight newborns were referred to our hospital for confirmatory diagnosis. Four other false-positive newborns were also referred. We compared the initial C5DC concentrations between affected and false-positive newborns, and there was no significant difference between the groups (p = 0.16) (Table 1).

    T1-10
    Table 1:
    Laboratory features of the group affected by glutaric aciduria type 1 and the false-positive group.

    3.2. Carnitine loading test

    C5DC concentrations prior to and after the carnitine loading test are shown in Table 1. A significant elevation in C5DC concentrations after the test was observed in all affected newborns, but not in false-positive newborns. The differences in C5DC concentrations prior to and after the test (C5DCafter test − C5DCprior to test) of the affected and false-positive newborns were statistically significant (p = 0.004) (Table 1). These findings indicate that the carnitine loading test is able to assist with the diagnosis of GA-1. Free carnitine (C0, unit: μM, normal: >8.00) concentrations were available for several individuals (prior to test, case 3: 12.57, case 4: 12.72, false-positive newborn 1: 17.81, newborn 2: 17.7, newborn 3: 23.26, after test: case 3: 110, case 4: 53.13, false-positive newborn 1: 49.03, newborn 2: 39.45, newborn 3: 24.01), and there was no significant difference between the affected and false-positive groups. Nevertheless, a trend towards an elevation of C0 for both groups was present after the test, although this was not statistically significant (affected group: p = 0.33, false-positive group: p = 0.1).

    3.3. Patient profiles and genetic diagnosis

    Since October 2002, eleven patients with GA-1 had received follow-up at our hospital. Nine were diagnosed by newborn screening. Two were born before the nationwide screening and were diagnosed clinically. Clinical and laboratory data are presented in Table 2.

    T2-10
    Table 2:
    Clinical information and genetic investigation of the eleven patients with glutaric aciduria type 1 (GA-1).

    DNA testing on ten patients revealed nine different mutations. Among these, two were novel mutations, namely T36fs (c.106delCA) and N291K (c.873C>A). The mutation T36fs is located in exon 2 and causes frameshifting. The missense mutation N291K is located in exon 8, and its effect on the function of glutaryl CoA dehydrogenase is predicted as damaging by Sorting Intolerant From Tolerant (http://sift.jcvi.org) and probably damaging by Polymorphism Phenotyping version 2 (http://genetics.bwh.harvard.edu/pph2). In our study, IVS10-2A>C was the most common (12/20 alleles), and R386X (c.1156C>T) was the second most common (2/20 alleles).

    3.4. Clinical manifestations

    Cases 1–9 were diagnosed by newborn screening. Case 1 was noted as having pendular nystagmus from 5 months of age, with a reduction in vision, oscillopsia, exotropia, refractive error, and amblyopia. Fundus examination and brain MRI revealed bilateral optic atrophy (Fig. 1A). Visual field examination revealed bilateral relative central scotoma. The treatment included spectacles, patching, and recession of bilateral lateral rectus muscle. Her visual acuity improved gradually. She had normal intelligence. Case 2 was noted as having pendular nystagmus from 7 months of age. Fundus examination was normal. Brain MRI showed T2 hyperintensity within the left occipital lobe, which may have been related to the disease or unmyelination (Fig. 1B). She was within the borderline intelligence range. Cases 3–5 achieved their normal developmental milestones. Case 6 was followed in another hospital and referred to our clinic at 8 years of age. She exhibited trivial involuntary shoulder movement and an unstable gait, but this did not cause disability. She had studied at mainstream schools.

    F1-10
    Fig. 1:
    Nystagmus workup. Brain MR (A) Axial T2-weighted MRI scan in case 1 at 5.9 years of age reveals bilateral optic nerve atrophy (black arrow). (B) Axial T2-weighted image in case 2 at 4.2 years of age reveals a high signal within the left occipital lobe (arrow), which may be related to the disease or unmyelination.

    Case 7 developed seizures and dystonia at 5 months of age, owing to poor intake for several days at home. She died unexpectedly at 1 year of age at a local hospital. Case 8 suffered from bronchopneumonia at 1.2 years of age. He showed decreased appetite for 2 days at home, which was followed by seizures, dystonia, dyskinesia, and developmental regression. His condition has improved gradually after treatment. At 1 year of age, case 9 showed decreased appetite for 2 days at home, which was followed by seizures. Frequent myoclonic jerks have been noted since then. She has mental retardation.

    Cases 10 and 11 were diagnosed clinically. Case 10 was found to have increased intracranial pressure and a subdural hematoma at 2 months of age. A ventriculoperitoneal shunt was implanted. Left hemiparesis and dystonia were found. GA-1 was diagnosed at 14 years of age, and she was referred to our clinic. Although she has been assessed as just being in the borderline intelligence range, she has still been able to study at university. Case 11 had suffered from macrocephaly since the prenatal period. He suffered from a seizure, rigidity, and dystonia following respiratory infection at 6.5 months of age. A brain CT revealed bilateral subdural effusion. Subdural-peritoneal shunts were implanted. He was referred to our clinic at 8.5 months of age and GA-1 was diagnosed. He became ventilator dependent and died from sepsis at 7.3 years of age.

    3.5. Growth

    In our study, 45% of patients showed macrocephaly (head circumference >97th percentile). Anthropometric parameters for 0 to 5 years of age were compared between patients with or without an encephalopathic crisis. Weight gain was greater among patients without a crisis (p = 0.04). A similar trend was revealed for height, but this showed no significant difference (p = 0.16).

    3.6. Outcome

    The frequency of encephalopathic crisis was 100% among the clinically diagnosed patients and 22% among the patients diagnosed by newborn screening. Patients were grouped into: (1) diagnosed by NBS with good compliance: cases 1–6; (2) diagnosed by NBS with poor compliance: cases 7–9 (delayed emergency treatment for 2 days or more); and (3) diagnosed clinically: cases 10 and 11. Cognitive functioning and disability scores for each patient are shown in Table 2. The cognitive functioning of the three groups were significantly different (p = 0.007). Dunn's multiple comparison test revealed a significant difference between group 1 and 2 (p = 0.03). The mean score was 101.8 for group 1, and 67 for group 3, but Dunn's multiple comparison test showed no statistical significance (p = 0.47), possibly due to the small sample size. These results suggest that newborn screening, followed by good compliance, is important to obtaining a good outcome among GA-1 patients.

    3.7. MRI findings

    The brain MRI investigations were classified into four groups: (1) infantile stage, namely surveys of eight patients (cases 1–5, 7–9), among whom seven were evaluated before 1 month of age and the other at 3.5 months of age; (2) just after an encephalopathic crisis, namely surveys of three patients (cases 7, 8, 11), performed 1 week to 2 months after the crisis; (3) encephalopathic crisis with long-term follow-up, namely surveys of three patients (cases 8, 10, 11) performed long after crisis; and (4) without crisis with follow-up, namely surveys of four patients (cases: 1, 2, 6, 9). At infantile stage, the MRI surveys revealed widening of the sylvian fissure (8/8, 100%). Just after an encephalopathic crisis, T2 hyperintensity at putamen, caudate nucleus, globus pallidus, and supratentorial white matter was noted (3/3, 100%). DWI and ADC maps showed restricted diffusion, mainly affecting the globus pallidus (3/3, 100%) and putamen (2/3, 67%). In addition, subdural hematoma and hygroma were also noted (1/3, 33%). The long-term follow-up MRI of patients after an encephalopathic crisis showed T2 hyperintensities within the supratentorial white matter (3/3, 100%), the presence of dilated ventricles (2/3, 67%) and atrophy of the putamen (2/3, 67%), caudate nucleus (2/3, 67%), and globus pallidus (2/3, 67%). There was no restricted diffusion on the DWI and ADC maps except within the affected supratentorial white matter (2/2, 100%) and putamen (1/2, 50%). Follow-up MRI of patients without crisis revealed T2 hyperintensity (4/4, 100%) and restricted diffusion (3/4, 75%) within the supratentorial white matter. T2 hyperintensity was also noted within the globus pallidus (2/4, 50%). The MRI findings are presented in Table 3. Fig. 2 demonstrates the characteristic changes at the different stages of the disease.

    T3-10
    Table 3:
    Patterns of MRI abnormalities at different stages of the disease.
    F2-10
    Fig. 2:
    MRIs of patients with GA-1 at different stages of the disease. (A) Infantile stage: Brain MRI of case 4 at 3 weeks of age. The T2-weighted image reveals widening of bilateral sylvian fissures (black arrow). (B–D) Just after an encephalopathic crisis: The brain MRI of Case 11 at 6.5 months of age; (B) T2-weighted image reveals hyperintensities affecting bilateral putamen, caudate nucleus, and globus pallidi (arrow). Bilateral subacute subdural hematoma can be seen within the frontotemporoparietal region (black arrowhead). (C–D) Diffusion-weighted imaging (DWI) (b = 500) and apparent diffusion coefficient (ADC) maps show restricted diffusion affecting bilateral putamen, caudate nucleus, and globus pallidi (arrow). (E) Encephalopathic crisis, follow-up: Brain MRI of Case 11 at one year after an encephalopathic crisis; T2-weighted image shows ventricular dilation (black arrowhead) and atrophy changes affecting the bilateral putamen and caudate nucleus (arrow). (F) Without encephalopathic crisis, follow-up: Brain MRI of Case 2 at 4 years of age; the T2-weighted image reveals hyperintensities affecting the deep white matter (black arrow).

    4. Discussion

    The incidence of GA-1 in this Taiwanese population was 1 in 106,474, which is approximately equivalent to the worldwide incidence (˜1 in 100,000).24 We identified nine mutations in twenty independent alleles, including two novel mutations, T36fs and N291K. The mutation IVS10-2A>C was the most common, which is compatible with previous Taiwan and Hong Kong studies.14,15,17,25 Six of our mutations have not previously been reported in Taiwan, but they have been reported in Hong Kong (IVS3+1G>A), Germany (R386X/R128Q), Turkey (R128Q), the USA (A421T/R355C) and the Netherlands (G354S).3,4,25,26 Our study enhances understanding of GA-1 mutations in Taiwan, thus helping mutational analysis.

    DWI and ADC maps are more sensitive when detecting acute/progressing brain damage than is conventional brain MRI.27 DWI and ADC maps help to differentiate between cytotoxic (restricted diffusion) from vasogenic brain edema (increased diffusion).27 Only a few studies have included DWI and ADC maps in their analysis of GA-1 patients.28–30 We used DWI and ADC maps to analyze brain damage; it was found that the brain edema in our patients was mainly cytotoxic edema. On analyzing the MRI features at different stages, it was found that infants as young as 12 days showed significant brain MRI abnormalities, such as widening of the sylvian fissure. This finding is consistent with the previous concept that GA1 brain damage starts prenatally.31

    We used MRI images taken 1 to 8 weeks after a crisis to explore basal ganglion involvement and found restricted diffusion at the basal ganglion. This finding suggests that cytotoxic damage to the basal ganglion persists post-crisis. When MRI images were obtained much longer after crisis, restricted diffusion was not found at the basal ganglia, but rather atrophied changes were present (Table 3). The disappearance of restricted diffusion suggests that the acute insult affecting the basal ganglion has disappeared gradually, and this is accompanied by basal ganglion atrophy due to neural death.32 T2 hyperintensities in white matter were prevalent among older patients, both with or without encephalopathic crises. The neuropathological implications of the presence of white matter disease in relation to GA-1 seems to involve spongiform myelinopathy, which is supposed to be caused by toxins associated with GA-1 that cause desmyelination or demyelination.33–36

    Our study suggests that the frequency of encephalopathic crisis decreases notably after newborn screening. This is compatible with previous reports.37–39 However, despite early treatment, 22% of patients still suffered from an encephalopathic crisis. This frequency is similar to that of presymptomatically diagnosed patients worldwide, which is around 25%.5 Among the nine patients diagnosed by newborn screening, the outcomes of cases 1–6 were much better than those of cases 7–9. Cases 7–9 had delayed emergency treatment, which is consistent with a German study showing that adherence to the maintenance treatment and early emergency treatment improves the neurological outcome, with all reported crises only occurring in patients when emergency treatment had been delayed for more than 24 hours after the initial symptoms.7 Additionally, different levels of disease severity were noted after an encephalopathic crisis. For example, Case 10 had an encephalopathic crisis at 2 months of age, but the diagnosis of GA-1 was delayed until 14 years of age. Despite some disability, she was still able to study at university. Her genotype included one Chinese hot spot mutation, IVS10-2A>C and one novel mutation N291K. We suspect that N291K is a milder mutation because of the more limited disease course. Nevertheless, recent studies suggest that there is no clear relationship between genotype and clinical phenotype.5,40 Interestingly, cases 1, 8, and 9, homozygous for IVS10-2A>C, had significantly different outcomes.

    Uniquely, two GA1 patients (cases 1, 2) had nystagmus; this has never been reported in pediatric GA1 patients. Nystagmus may be caused by cortical visual impairment and/or optic atrophy.41–43 Importantly, several inherited metabolic disorders cause cortical visual impairment or optic atrophy.42,44 Optic atrophy or nystagmus has been reported in patients with organic aciduria, such as cobalamin C defects, methylmalonic aciduria or isovaleric aciduria.45,46 We suggest that GA-1 might be a new etiology of nystagmus. Our examinations revealed optic atrophy affecting case 1 and the presence of T2 hyperintensity within the left occipital lobe in case 2, which might be related to the disease or unmyelination. Therefore, although cortical visual impairment was suspected as a cause of the nystagmus affecting case 2, the actual etiology of that case remains undetermined. Additionally, nystagmus had been reported in one patient with adult onset GA-1 who presented with leukoencephalopathy.47 Cataract, intraretinal hemorrhages, strabismus, gaze palsy, pigmentary retinopathy, and ametropia have also been reported in GA-1 patients.48 However, optic atrophy has never been reported in GA1 patients; ours is the first reported. Therefore, complete ophthalmological evaluations are suggested when examining patients with GA-1. The pathophysiology of the optic atrophy detected in case 1 remains unknown, but we suggest that it is similar to the white matter disease, namely spongiform myelinopathy, which is induced by toxins associated with GA-1. This suggestion is based on a GA-1 autopsy report, which demonstrated the presence of spongiform myelinopathy of the optic nerve.34 Furthermore, in vitro studies and animal studies also support the hypothesis that GA and its metabolites cause white matter disease in GA-1 patients.35,36 Although GA-1 nervous system damage starts prenatally, early treatment in case 1 was able to produces a gradual improvement in visual acuity.

    Missed cases have been reported who had an initially elevated C5DC concentration that normalized on a repeated sample.18,19 Such a result may be caused by secondary carnitine depletion. To avoid carnitine depletion, we propose that the carnitine loading test be used to assist diagnosis of GA-1. Although, so far, we have not identified any missed patients, our study did reveal that the carnitine loading test brought about a significant elevation of C5DC in GA-1 patients. We believe this should help to reduce false negative results caused by secondary carnitine depletion.

    In conclusion, our results support the idea that early diagnosis by newborn screening followed by complete fulfillment of treatment guidelines is important to a good outcome. In addition, the carnitine loading test would seem to be an appropriate adjuvant diagnostic method. Moreover, new presentations of GA-1, namely nystagmus and optic atrophy, have been identified, which should help to improve management of this disease.

    Acknowledgements

    We thank the Taipei Institute of Pathology and the Chinese Foundation of Health for performing the newborn screening and providing the statistical data.

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    Keywords:

    glutaric aciduria type 1; newborn screening; nystagmus; optic atrophy; Taiwan

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