Journal of Perinatology (2012) 32, 810–813 r 2012 Nature America, Inc. All rights reserved. 0743-8346/12 www.nature.com/jp
PERINATAL/NEONATAL CASE PRESENTATION
Neonatal presentation of lethal neuromuscular glycogen storage disease type IV LF Escobar1,2, S Wagner1, M Tucker1,3 and J Wareham2 1
Medical Genetics and Neurodevelopmental Pediatric Center-Peyton Manning Children Hospital, Indianapolis, IN, USA; 2Section of Neonatology-St Vincent Women’s Hospital, Indianapolis, IN, USA and 3Center for Prenatal Diagnosis-St Vincent Women’s Hospital, Indianapolis, IN, USA
A total of 11 types of glycogen storage disorders have been recognized with variable clinical presentations. Type IV, also known as Andersen disease, represents a rare subtype that can induce severe clinical findings early in life. We report on a patient with early fetal onset of symptoms with severe neuromuscular findings at birth. The pregnancy was further complicated by polyhydramnios and depressed fetal movement. At birth severe hypotonia was noticed requiring active resuscitation and then mechanical ventilation. His lack of expected course for hypoxic ischemic encephalopathy prompted genetic testing, including a muscle biopsy, which confirmed the diagnosis of glycogen storage disease IV (GSD IV). Mutation analysis of the glycogen branching enzyme 1 gene demonstrated a previously unrecognized mutation. We review recent information on early presentation of GSD IV with particular interest in the presentation of the neonatal lethal neuromuscular form of this rare disorder. Journal of Perinatology (2012) 32, 810–813; doi:10.1038/jp.2011.178
Keywords: glycogen storage disease; hypotonia; fetal akinesia; Andersen syndrome
Introduction Glycogen storage disease IV (GSD IV or Andersen disease) accounts for only 3/1000 of all GSD’s and 1 in 7 60 000 to 9 60 000 live births.1 It is an autosomal recessive metabolic disorder caused by mutations in the glycogen branching enzyme gene (GBE1). The glycogen branching enzyme is vital for glycogen synthesis, and when deficient results in the accumulation of amylopectin-like configurations of glycogen in the liver, heart, muscle, nervous system and skin.2 GBE1 is located at chromosome 3p14 and encodes for a 702 amino-acid protein.1,3–5 GSD IV usually presents in the first year of life with features of hepatic failure and portal hypertension, normally causing death by the age of 2 to 4.3 Few cases have been reported in the literature of the early severe Correspondence: Dr LF Escobar, Medical Genetics/Neonatology, Peyton Manning Children’s Hospital, 8402 Harcourt Road, #300, Indianapolis, IN 46260, USA. E-mail: [email protected]
Received 27 September 2011; revised 1 November 2011; accepted 2 November 2011
presentation of GSD IV, which resembles spinal muscular atrophy type 1 (SMA1) in the newborn.6 The presentation of GSD IV resembling SMA1 is considered a severe neuromuscular subtype of GSD IV. We report on case of an unusual presentation of GSD IV neuromuscular type with a severe lethal phenotype in the neonatal period. The condition appears to be caused by a previously unrecognized mutation in the GBE1 gene. We did not recognize a second mutation, suggesting the possibility of homozygosity for the new mutation, consanguinity or uniparental disomy. We review additional published cases, and discuss the need for awareness that severe neonatal hypotonia with a lack of spontaneous movement may represent GSD IV, neuromuscular type.7
Patient summary We report on male patient born at 35 weeks gestation to a 30-year-old primigravida mother after a pregnancy complicated by polyhydramnios, perinatal depression and a vague history of recent decrease fetal movement. The birth weight was 2.300 kg (28 percentile), the length was 46 cm (47.2 percentile) and the head circumference was 31 cm (36 percentile). Upon delivery, the child exhibited severe hypotonia with no spontaneous movement, bradycardia and apnea. Apgar scores were 0, 1 and 1 at 1, 5 and 10 min, respectively. Resucitation including CPR, intubation, multiple doses of epinephrine and volume expansion lasted 18 min. Once heart rate stabilized the infant was transferred to the NICU and was placed on mechanical ventilation. Upon clinical examination, the patient showed marked hypotonia and poor response to stimuli. There was decreased muscle mass with no peripheral reflexes, normocephaly with a soft open anterior fontanel, normal fundoscopy, patent nares, a normal oral cavity, clear breath sounds, a regular heart rate and good pulses. The abdomen was soft and symmetric, displaying no organomegaly. However, there was anterior displacement of the anal ampulla, which was also hypotrophic with decreased anal folds, suggestive of decreased muscle mass.
Neonatal presentation of lethal neuromuscular GSD IV LF Escobar et al
After 2 weeks without spontaneous movement even while weaning sedation, rare causes of severe neuromuscular dysfunction other than hypoxic ischemic encephalopathy were considered. A chest X-ray showed mild atelectasis in the right upper lobe and left posteromedial lung base. A head MRI demonstrated a prominent fluid collection posterior to the cerebellar hemisphere, indicating the presence of a mega cisternal magna. A complete spinal MRI noted an unremarkable spinal cord. Testing for both SMA1 and congenital muscular dystrophy (DM1) was negative. A comparative genomic hybridization was normal with no copy number variants of clinical significance. A urine amino-acid screening showed non-specific elevations of cystine, ornithine, lysine and arginine. A second amino-acid screening and a urine screening found 18 amino acids with elevated levels and 29 organic acids with higher than normal levels. Neither of these analyses indicated a clear pathologic pattern. Due to the unclear etiology of the severe muscle symptoms we did a muscle biopsy. The biopsy showed significantly atrophic muscle fibers and an increased density of the nuclei. Central nuclei were observed in scattered fibers, and basophilic, pale and even degenerating fibers were also observed. Additionally, the muscle biopsy showed numerous inclusions staining positively for periodic acid schiff (PAS). The PAS-positive inclusions were also observed to be resistant to diastase digestions (Figure 1). These findings were indicative of a glycogen storage disorder. Subsequently, we undertook enzymatic studies testing for GSD type II and GSD type IV. The glycogen storage investigation
indicated normal ranges for the glycogen content (patient: 0.2%, control: 0.94±0.55%) and alpha glucosidase activity (patient: 0.59 mmol min1 per gram tissue, control: 0.42± mmol min1 per gram tissue) in the muscle sample possibly due to the early stages of disease, whereas the branching enzyme activity was measured in the very low deficiency range (patient: 0.3 mmol min1 per gram tissue, control: 32±10 mmol min1 per gram tissue). A deficiency in the glycogen-branching enzyme suggested GSD IV. Following the above studies, we obtained a skin biopsy to sequence the GBE1 gene known to cause glycogen storage disorder type IV. Sequencing found a previously unreported mutation consisting of a single amino-acid substitution (c.1236 þ 1 G>A). Following two sudden cardiac crises, the patient died at age 117 days (3.8 months) of age. Maternal testing showed mother to be positive for the same mutation, and paternal testing was not possible. Discussion GSD IV is a rare metabolic disorder, where there is a deficiency in the glycogen branching storage enzyme. The normal form of the glycogen branching enzyme catalyzes the movement of glucose molecules from the end of a glycogen chain to an alpha-1,6 position on the chain, forming an alpha-1,6 glycosidic bond between two glucose molecules. A deficiency in this enzyme results in a glycogen chain with fewer branching points and
Figure 1 Periodic acid schiff (PAS) staining of quadriceps muscle biopsies from a control patient (a) and patient affected by glycogen storage disorder type IV (b). Diastase treated, PAS stained section of quadriceps muscle biopsies from control tissue (c), and tissue of a patient diagnosed with glycogen storage disorder type IV (d). Journal of Perinatology
Neonatal presentation of lethal neuromuscular GSD IV LF Escobar et al
812 Table 1 Features of patients with the lethal GSD IV reported in the literature Number of patients (N ¼ 29)
Prenatal symptoms Polyhydramnios Hydrops fetalis Decreased fetal movement
18/29 11/29 15/29
62 41 52
Postnatal symptoms Neuromuscular findings Respiratory findings Cardiac findings Other dysmorphic features
19/29 22/29 10/29 6/29
66 76 34 21
PAS-positive deposits Decreased glycogen branching enzyme activity Mutation in branching enzyme gene Mortality rate
Abbreviations: GSD IV, glycogen storage disease type IV; PAS, periodic acid schiff.
longer outer chains.8 This abnormally branching glycogen, often referred as amylopectin, accumulates in all tissues disrupting the integrity of the muscle fibers.9 In GSD IV there is considerable variation in clinical presentation and course making it difficult to diagnose. GSD IV can present as a progressive form leading to liver failure by the age of five, a milder non-progressive hepatic form, a variant with multi-system involvement, a juvenile form with the amylopectin-like glycogen but normal glycogen branching enzyme functioning and lastly the lethal neonatal neuromuscular presentation. The lethal neonatal form can be associated with pregnancies complicated by polyhydramnios, hydrops fetalis and limited fetal movement secondary to severe myopathy, hypotonia and poor fetal growth. The 29 published and documented cases of fatal congenital GSD IV and their clinical findings are summarized in Table 1. The case discussed here presented with severe findings that were not specific to but consistent with GSD IV. Our patient was delivered after a pregnancy complicated with polyhydramnios and possibly depressed fetal movement. The majority of confirmed cases of GSD IV in the literature presented with polyhydramnios during the fetal period (Table 1), most often occurring during the third trimester. In addition to polyhydramnios, our patient presented with decreased fetal movement late in the pregnancy. Half of the documented cases report decreased fetal movement (Table 1). Both the polyhydramnios and decreased fetal movement are likely to be a result of the accumulation of the amylopectin-like glycogen in the skeletal muscles, causing hypotonia. The muscle weakness likely prevents proper swallowing, inducing polyhydramnios. Hydrops fetalis has also been seen in patients diagnosed with GSD Journal of Perinatology
IV (Table 1). Maruyama et al.10 report a case of GSD IV with hydrops fetalis, which was postnatally attributed to chylothorax. Hydrops fetalis may be the result of decreased movement resulting from hypotonia that hinders lymphatic drainage.9 At birth, our patient presented with severe hypotonia, poor response to stimuli and very little spontaneous movement. Eighty-five percent of live born infants diagnosed with the lethal neonatal neuromuscular form of GSD IV, including our case, presented with hypotonia at birth. This is one of the hallmark of glycogen storage disorder type IV, resulting from the accumulation of the improperly branching glycogen in neuronal and skeletal muscle tissues.9,11 Seventy-six percent of cases, including our case, required immediate intubation and mechanical ventilation, a direct result of muscle dysfunction and poor respiratory effort. In addition to respiratory findings, cardiac dysfunction, likely due to the accumulation of abnormal glycogen in the myocardial tissues was seen (Table 1). Two cases had cardiomyopathy as a significant cardiac finding.7,12 Dysmorphic features were also reported following birth in 21% of the cases (Table 1), including a cleft palate in one case and features resembling Crouzon syndrome in another case.1,13 All 29 reported patients with neuromuscular neonatal GSD IV died, with the longest living patient surviving to 28 months.13 All patients’ deaths were linked to complications due to muscle weakness, most frequently involving myocardial and skeletal muscle and resulting in cardiac and respiratory failure.9 Enzymatic assays and staining for glycogen deposits are required to make a conclusive diagnosis of glycogen storage disorder type IV. In suspected cases of GSD IV, an enzyme activity assay should be performed to determine the activity of the glycogen branching enzyme. From all patients reviewed, 18 of 29 cases had enzyme assay performed and all had decreased glycogen branching enzyme activity. The decrease in enzyme activity in these cases was most often demonstrated in fibroblasts (others did not specify tissue source).4,9,11,13–15 Other tissues reported to have decreased branching enzyme activity include the central nervous system, white blood cells, epidermis and muscle. In all, 24 of the 29 cases had PAS testing and all had PAS þ inclusions in various muscle tissues. This indicates a significant increase in glycogen storage in muscle fibers. Additionally, our patient’s muscle biopsy was stained with diastase and found to be resistant to diastase digestion, also suggesting an abnormal glycogen structure. In all, 11 of the 29 cases had sequencing the GBE gene and reported at least one mutation in the gene. Sequencing on our patient identified a single mutation consisting of an amino-acid substitution c.1236 þ 1 G>A. This mutation has not been previously reported. Although the exact impact of this novel mutation is unknown, it is similar to previously reported GBE1 gene mutations. This particular variant disrupts a GT splice site. Akman and Konstanidou, both report on a novel splice site mutation at the intron exon boundary of exon 11, which likely caused mRNA instability or abnormal splicing.1 Multiple cases of
Neonatal presentation of lethal neuromuscular GSD IV LF Escobar et al
GSD IV have been reported with mutations that cause a truncated version of the glycogen branching enzyme that causes reduced to no enzyme functionality.1,4,6,7,12,16–18 As GSD IV is an autosomal recessive disorder, we suspect that our patient has a second unidentifiable mutation in the GBE1 gene. Uniparental disomy, consanguinity and a deletion could be considered as a likely explanation.19,20 In summary, we report a previously unrecognized mutation in the GBE1 gene causing a lethal neonatal neuromuscular form of GSD IV (Andersen disease). Clinicians in the NICU should be aware of the role of GSD IV in the causation of severe hypotonia in the neonatal period, which is unresponsive to conventional therapy. Additionally clinicians should consider GSD IV when pregnancies are complicated by polyhydramnios, hydrops fetalis and/or depressed fetal movement despite the rarity of the disease. Conflict of interest The authors declare no conflict of interest.
We would like to thank Dr David Weaver for reviewing this manuscript and for his excellent advice.
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