Brain tissue- and region-specific abnormalities on volumetric MRI scans in 21 patients with Bardet-Biedl syndrome (BBS)

Abstract

BackgroundBardet-Biedl syndrome (BBS) is a heterogeneous human disorder inherited in an autosomal recessive pattern, and characterized by the primary findings of obesity, polydactyly, hypogonadism, and learning and behavioural problems. BBS mouse models have a neuroanatomical phenotype consisting of third and lateral ventriculomegaly, thinning of the cerebral cortex, and reduction in the size of the corpus striatum and hippocampus. These abnormalities raise the question of whether humans with BBS have a characteristic morphologic brain phenotype. Further, although behavioral, developmental, neurological and motor defects have been noted in patients with BBS, to date, there are limited reports of brain findings in BBS. The present study represents the largest systematic evaluation for the presence of structural brain malformations and/or progressive changes, which may contribute to these functional problems.MethodsA case-control study of 21 patients, most aged 13-35 years, except for 2 patients aged 4 and 8 years, who were diagnosed with BBS by clinical criteria and genetic analysis of known BBS genes, and were evaluated by qualitative and volumetric brain MRI scans. Healthy controls were matched 3:1 by age, sex and race. Statistical analysis was performed using SAS language with SAS STAT procedures.ResultsAll 21 patients with BBS were found to have statistically significant region- and tissue-specific patterns of brain abnormalities. There was 1) normal intracranial volume; 2) reduced white matter in all regions of the brain, but most in the occipital region; 3) preserved gray matter volume, with increased cerebral cortex volume in only the occipital lobe; 4) reduced gray matter in the subcortical regions of the brain, including the caudate, putamen and thalamus, but not in the cerebellum; and 5) increased cerebrospinal fluid volume.ConclusionsThere are distinct and characteristic abnormalities in tissue- and region- specific volumes of the brain in patients with BBS, which parallel the findings, described in BBS mutant mouse models. Some of these brain abnormalities may be progressive and associated with the reported neurological and behavioral problems. Further future correlation of these MRI scan findings with detailed neurologic and neuropsychological exams together with genotype data will provide better understanding of the pathophysiology of BBS.

Brain involvement in Alström syndrome

“…Though the exact function of cilia in brain development is unclear, expression of genes involved in ciliary transport are seen in developing neural tissues. A recent MRI study investigated the brain in BBS, a ciliopathy that is clinically similar to AS with the exceptions of polydactyly and learning deficits [27]. By means of volumetric analisys, the study disclosed a significant decrease of white matter volume, suggesting a primary white matter involvement in this ciliopathy.…”

“…In this region, AS patients had increased mean and radial diffusivity consistent with axonal involvement. It has been demonstrated that body mass index correlates positively with mean and radial diffusivity in the fornix [28]. Moreover, in several psychiatric diseases (e.g.…”

Structural defects in cilia of the choroid plexus, subfornical organ and ventricular ependyma are associated with ventriculomegaly

“…A recent study of 21 BBS patients showed statistically significant increased CSF volume in both the surface of the brain and in the ventricles [14]. BBS is caused by at least 17 genes, which, when individually mutated, give rise to common phenotypes [[13,15-18]; and references therein].…”

Primary cilia in neurodevelopmental disorders

“…23,24 Several studies have reported the occurrence of hydrocephalus and a reduction in hippocampal volume in patients with BBS, defects that are also seen in several mouse models of BBS. 25–31 …”