Natural history of Christianson syndrome

Abstract

Christianson syndrome is an X-linked mental retardation syndrome characterized by microcephaly, impaired ocular movement, severe global developmental delay, hypotonia which progresses to spasticity, and early onset seizures of variable types. Gilfillan et al.2008] reported mutations in SLC9A6, the gene encoding the sodium/hydrogen exchanger NHE6, in the family first reported and in three others. They also noted the clinical similarities to Angelman syndrome and found cerebellar atrophy on MRI and elevated glutamate/glutamine in the basal ganglia on MRS. Here we report on nonsense mutations in two additional families. The natural history is detailed in childhood and adult life, the similarities to Angelman syndrome confirmed, and the MRI/MRS findings documented in three affected boys.

FIG. 1

Partial pedigree of Family 1 (K8310), showing six affected males in two generations and three carrier females in three generations.

FIG. 2

Facial appearance of five of the six affected males in Family 1 (K8310) and the single affected male in Family 2 (K9524). III-9 at age 35 years showing frontal upsweep, strabismus, open mouth and prominent jaw. III-12 at age 28 years showing microcephaly, upsweep of frontal hair, thin and gaunt face, low nasal septum, open mouth and abnormal hand posturing. IV-1 at age 15 years showing microcephaly and hypotonic face with open mouth. IV-4 at age 6¹¹/₁₂ years showing microcephaly and frontal upsweep of hair, but otherwise normal face. IV-6 at age 14 months showing microcephaly, upswept frontal hair, triangular face, wide mouth and thin upper lip. The isolated case in Family 2 is shown at age 6 years with microcephaly and hypotonic face with open mouth.

FIG. 3

Bilateral abnormal horizontal eye movements in IV-I (family 1, K831) when looking to the right (A) and to the left (B). Although there were occasions that the eyes could almost be laterally buried, the majority of the time he exhibited a bilateral cranial nerve VI paresis on examination.

FIG. 4

Brain magnetic resonance imaging on maternal half-brothers (IV-1 and IV-4, Family 1, K8310) using a 1.5 T magnet. A,B: Sagittal T1-weighted and coronal FLAIR images respectively on IV-4 at age 7 years. C,D: sagittal T1-weighted and coronal FLAIR images on IV-1 at age 14 years. A,C: Volume loss secondary to focal atrophy and/or hypoplasia of the inferior cerebellar vermis with prominent cerebral spinal fluid space at the cisterna magna in both patients (curved white arrows). The volume loss secondary to focal atrophy and/or hypoplasia is more conspicuous in the oldest patient, IV-1. B,D: Subtle abnormally high signal in the inferior aspect of the cerebellar hemispheres on coronal FLAIR sequences in IV-4 and IV-1 (straight white arrows) which may indicate some degree of gliosis.

FIG. 5

Transverse spin-echo T2-weighted magnetic resonance images of the brain. A,B: Prominent lateral ventricles in IV-1. Brain MRI coronal FLAIR (Fluid Attenuation Inversion Recover) images. C,D: Mild reduction in size and increase signal of the hippocampi (white arrows image C) in IV-1 in comparison to image D which shows normal size and signal of the hippocampi on IV-4 (black arrows).

FIG. 6

Single voxel short echo time magnetic resonance spectroscopy (MRS) performed in a 1.5 T magnet (TE: 25–30 ms) demonstrated a strikingly similar abnormally prominent Glutamate/Glutamine shoulder (arrows) in all three spectra. The volumes of interest are located in the left basal ganglia in IV-4 (A), the left basal ganglia in IV-1 (B), and the left parietal white matter in IV-1 (C). The illustrations in the panels on the right indicate the position of the voxels. Standard spectral peaks are illustrated for inositol (Ins), choline (Cho), creatine (Cr), and N-acetylaspartate (NAA).