MECP2 Duplication Syndrome in a Patient from Cameroon

Abstract

MECP2 duplication syndrome (MDS; OMIM 300260) is an X-linked neurodevelopmental disorder, caused by nonrecurrent duplications of the Xq28 region involving the gene methyl-CpG-binding protein 2 (MECP2; OMIM 300005). The core phenotype of affected individuals includes infantile hypotonia, severe intellectual disability, very poor-to-absent speech, progressive spasticity, seizures and recurrent infections. The condition is 100% penetrant in males, with observed variability in phenotypic expression within and between families. African patients with Xq28 duplication involving MECP2 have scarcely been reported. Here, we describe a sub-Saharan African male patient from Cameroon, with MDS caused by an inherited 610kb microduplication of Xq28 encompassing the genes MECP2, IRAK1, L1CAM and SLC6A8. This report supplements public data on MDS and contributes by highlighting the phenotype of this condition in affected individuals of African descent.

1. INTRODUCTION

MECP2 is a dosage sensitive gene whose loss-of-function is known to cause Rett syndrome, a childhood progressive neurodevelopmental disorder affecting almost exclusively females. Duplication of the Xq28 region including the gene MECP2 has been identified in ~1% of males with unexplained X-Linked intellectual disability (Lugtenberg et al., 2009). MECP2 duplication syndrome (MDS), while sharing some clinical features with Rett syndrome, is a clinically and molecularly distinct entity, caused by overexpression of the protein methyl-CpG-binding protein-2 (MeCP2) as demonstrated in mice studies (Collins et al., 2004). The duplication of Xq28 varies in size, breakpoint locations and gene content among affected individuals, with MECP2 playing the major role in disease pathogenesis. MDS affects mostly males and the duplication is inherited from a non-affected mother in the majority of cases. Affected females have either a rearrangement of an X chromosome leading to a functional disomy of Xq28, or a random or unfavorable skewed X chromosome inactivation (XCI) with preferential silencing of the non-duplicated X chromosome (Ramocki, Tavyev, & Peters, 2010). Affected males with MDS classically present with infantile hypotonia, severe-to-profound intellectual disability, poor or absent speech, progressive spasticity predominantly of the lower limbs, various types of seizures, recurrent respiratory infections, behavioral issues, unsteady gait and dysmorphic features (brachrycephaly, deep-set eyes, midface hypoplasia, protruding ears, narrow nasal bridge, anteverted nares and open-mouth with frequent drooling) (Ramocki et al., 2010). Genitourinary and gastrointestinal abnormalities including chronic constipation are not infrequent. Here, we report on a Cameroonian male with an inherited duplication of the Xq28 region including MECP2.

2. CLINICAL REPORT

The patient was a 5-year-old boy referred for genetic assessment due to severe global developmental delay with absent speech, hypotonia, generalized tonic-clonic seizures and some dysmorphic features. He was the second of three children of an apparently healthy mother. The patient’s older brother reportedly died at the age of 8 years from intractable seizures and reportedly had a similar clinical presentation. His younger sister is otherwise healthy. The patient was born at 41 weeks’ gestation by normal vaginal delivery following an uneventful pregnancy. His Apgar score at one and five minutes was respectively 8 and 9. His birth weight was 3064g (25^th percentile), length 49cm (50^th percentile) and head circumference 34^th (50^th percentile). At the age of 3 months, the patient was reported to have feeding difficulties, floppiness, noisy breathing and sleep disturbance. He was subsequently diagnosed with adenoids hypertrophy, requiring adenoidectomy. During his first assessment at the age of 6 months in neurology, he was noticed to have axial hypotonia, developmental delay and mild dysmorphic features. At the age of 2 years, he developed generalized tonic-clonic seizures that were successfully controlled by carbamazepine. During a clinical genetics assessment at the age of 5 years, the patient presented with hypotonia, bilateral undescended testis, hypoplastic scrotum and severe global developmental delay with acquisition of only a single word from the age of 4 years. There was a history of chronic constipation and frequent hospital admissions for lower and upper respiratory tract infections. The craniofacial features observed were non-specific and included a broad face with full cheeks, deep-set eyes, midface retrusion, low-set ears, anteverted nares and open mouth with protruded tongue and frequent drooling (Figure 1a, b, c1, c2, c3). At the age of 6 years, he developed complex motor stereotypies with repetitive movements of the hand and arms. The course of the disease was complicated by progressive spasticity of the lower limbs, unusual posture with flexion of the trunk and knees (Figure 1d), unsteady gait, and neuroregression with complete loss of the patient’s single word speech at the age of seven. There was an exacerbation of seizures from 8 years, which became multidrug-resistant, resulting in frequent episodes of status epilepticus and hospital admissions. Magnetic resonance imaging (MRI) of the brain was unremarkable. Repeated electroencephalograms demonstrated multifocal wave spikes. The patient demised at the age of 8 years and 7 months following intractable seizures. Genetic investigations included G-banding karyotype which was normal (46,XY). Array-CGH subsequently performed on genomic DNA identified a duplication of Xq28 with a size of 610kb, encompassing the genes IRAK1, L1CAM, SLC6A8 and MECP2 (Figure 2). The patient’s mother and sister were found to be carriers of the same Xq28 duplication, with XCI studies showing a skewed pattern of inactivation toward the duplicated X chromosome which was extremely (>90%) inactivated in both of them.

Figure 1.

Craniofacial features and habitus of the patient. (a) image of the patient at the age of 1year showing a broad face with full checks, high forehead with high anterior hairline and a small open mouth. (b) front view of the face at 5 years showing midface retrusion, depressed nasal bridge and deeply set eyes with infra-orbital folds. (c1), (c2), (c3) facial features at 6 years showing sparse eyebrows, low-set ears, anteverted nares, open mouth with protruded tongue, and thick and everted vermillion of the lower lip. (d) photograph at 8 years of age showing patient’s usual posture with flexion of the trunk and knees. Written informed consent was obtained from the family for publication of these photographs.

Figure 2.

Results of array comparative Genomic Hybridization (array-CGH). Analysis performed on genomic DNA from the patient and his mother showing a duplication with a size of 610kb, spanning the region Xq28 with breakpoints located between positions 152,780,136 and 153,390,314 bp (GRCh37/hg19). The duplication encompasses 21 OMIM protein-coding genes (https://www.genome.ucsc.edu/cgi-bin/hgTables), including MECP2, IRAK1, L1CAM and SLC6A8.

3. DISCUSSION

This report presents for the first time a male patient from Cameroon, central Africa, identified with Xq28 duplication on array-CGH, resulting in MDS. The diagnosis of this patient was established during a genome-wide investigation for copy number variations, as a targeted diagnosis of MDS could be hardly hypothesized based on the patient’s dysmorphology and clinical presentation at our initial assessment. The phenotypic expression of MDS shows variability among affected individuals. Yet, although non-specific, cardinal clinical characteristics tend to be almost always present. These features include severe global developmental delay, early hypotonia, recurrent infection predominantly of the respiratory tract, behavioral issues and dysmorphic features. A retrospective assessment of the present patient considering the course of his disease showed that, except from some particularities in craniofacial dysmorphology (Figure 1a, b, c1, c2, c3), his clinical presentation was grossly similar to that described in patients from other populations (Miguet et al., 2018). As patients’ dysmorphology in several conditions may show variations across populations or ethnic groups (Kruszka et al., 2017), the more clinical data from African patients with MDS are publicly available, the better one would be able to powerfully establish any existing phenotypic specificity in African patients compared to patients from diverse populations.