A rare MeCP2_e1 mutation first described in a male patient with severe neonatal encephalopathy

INTRODUCTION

MECP2-related severe neonatal encephalopathy is a rare, exclusively male expression of mutations in MECP2 that would produce a Rett syndrome (RTT) phenotype in females. We describe a male neonate that presented with hypoventilation and seizures who upon subsequent investigation was found to harbor a mutation in exon 1 of MECP2, c.62 + 2_62 + 3delTG. To date, only three females with classic RTT and one female with a typical RTT have been documented to harbor this mutation [Christodoulou et al., 2003; Quenard et al., 2006], with this being the first to be found in a male manifesting any form of MECP2-related disease.

CLINICAL REPORT

The patient was a male born at 40 weeks gestation to a 26-year-old G3P1011 mother via repeat caesarean section after an uneventful pregnancy. Birth weight was 2,990 g (25–50th percentile), length 51 cm (75–90th percentile), head circumference 33 cm (25–50th percentile), and Ponderal index of 2.25 (<10th percentile). Apgar scores were nine and nine at 1 and 5–min, respectively. At 26 hr of life, the patient had a cyanotic episode and was transferred from the regular nursery to the neonatal intensive care unit (NICU).

Upon arrival, no dysmorphism was appreciated on physical examination, but global hypotonia and a negative vestibulo-ocular reflex were noted on neurological exam. His first arterial blood gas showed respiratory acidosis with a pH 7.17, a PO2 of 59 mmHg, a PCO2 of 52 mmHg, a HCO3 of 21.5 mmol/L, and a base excess of −7.8. Caffeine and non-invasive intermittent mandatory ventilation were started. His NICU course was punctuated by multiple apneic and hypopneic episodes associated with desaturations.

During his NICU stay, he remained hypotonic, gained weight poorly, and was intolerant to oral feeding. An electroencephalogram (EEG) revealed left more than right independent anterior temporal spikes and one burst of suppression preceded by an episode of myoclonic activity. However, these abnormalities did not correlate temporally with any apneic or hypopneic episodes. Computer tomography and magnetic resonance imaging of his brain were normal.

Additionally, a pneumogram was performed which showed 40 percent periodic breathing, suggesting a diagnosis of congenital central hypoventilation syndrome (CCHS); testing for PHOX2B mutation was negative, however. A karyotype was performed which was normal male (46,XY) and the New York Newborn Screen was negative for any of the screened diseases. Serum amino acid and urine organic acid levels revealed no pattern consistent with a known metabolic disease.

After discharge from the NICU, the patient was admitted back to the pediatric floor and to the pediatric intensive care unit (PICU) numerous times with diagnoses of apparent life threatening episodes (ALTE), status epilepticus, and prolonged apneic/hypopneic episodes which were numerous and unremitting.

Over time his head circumference percentile decreased to below the 10th centile. No stereotypic behaviors of any kind, including hand movements characteristic of RTT, ever developed. His hypotonia remained profound throughout life, and no developmental milestones in any modality were ever met. He remained gastrostomy-tube fed and in constant need of assistance with handling of respiratory secretions. Additionally, despite multiple admissions under video EEG surveillance for antiepileptic medication adjustment and titration, the patient's seizures were never fully controlled, with observable seizures occurring multiple times daily.

Part of the search for the etiology of this patient's persistent breathing abnormalities was the test for mutations in MECP2 which revealed the aforementioned mutation. The patient died at approximately 2 years of age.

MATERIALS AND METHODS

A PCR-based assay was used to amplify the region in which the mutation was identified. The amplified product was sequenced both in the forward and reverse directions using automated fluorescence dideoxy sequencing methods. The assay was performed at Baylor College of Medicine's Medical Genetics Laboratories.

DISCUSSION

We were not able to test the patient's mother, father, or sister for the detected mutation, nor do we know whether any testing was done on the mother's abortus from her second pregnancy. There was no history of RTT, any type of neurologic disease, learning disorders, or subtle forms of intellectual disability in any family member, including in the patient's older sister and mother. While the patient's mother may have been the carrier of the mutation, herself unaffected due to a favorable X-chromosome inactivation pattern, the mutation may also have spontaneously occurred in our patient.

To date, the mutations identified in patients with MECP2-related severe neonatal encephalopathy have been located in regions downstream from exon one of MECP2 (c.397C>t, c.401C>G, c.473C>T, c.488_489delGG, c.753dupC, c.806delG, c.808delC, c.1157_1200del44), and have not always been identified in sisters or mothers of the affected male patients [Wan et al., 1999; Villard et al., 2000; Geerdink et al., 2002; Zeev et al., 2002; Lynch et al., 2003; Leuzzi et al., 2004; Budden et al., 2005; Masuyama et al., 2005; Kankirawatana et al., 2006; Dayer et al., 2007].

In patients with typical/atypical RTT, Saunders et al. [2009] found MECP2 exon 1 mutations in an average of 8.1% of patients. The lower detection rate of mutations at this locus of MECP2 is thought to be due to the shorter coding sequence of exon 1 (62 vs. 1,435 nucleotides for exons 3 and 4 combined) [Quenard et al., 2006]. Exon 1 codes for the isoform of the Mecp2 protein that is 12 amino acids longer and 10 times more prevalent in the brain [Mnatzakian et al., 2004; Amir et al., 2005], with the specific mutation detected in our patient causing a two base pair deletion at the intron 1 donor splice site [Quenard et al., 2006]. The subsequent lack of normal gene product has been shown to cause abnormal maturation of both neurons and glia without initial gross neuroanatomic deficits, but ultimately resulting in microcephaly [Franke, 2006; Gonzalez and LaSalle, 2010].

Given the findings reported in this paper, exon 1 mutations can be included in the range of genotypes known to cause MECP2-related severe neonatal encephalopathy, and an expanded potential for better understanding of genotype–phenotype correlations exists in these patients. Kankirawatana et al. [2006] suggested that male patients with two or more of the following findings should be tested for MECP2 mutations: moderate or severe early postnatal, progressive encephalopathy; unexplained central hypoventilation or respiratory insufficiency; abnormal movements; intractable seizures; abnormalities in tone. In light of the expanded number of MECP2 mutations in males that now includes those in exon 1, this suggested approach has added weight [Villard, 2007].