Brain involvement in Alström syndrome

Alström syndrome (AS; OMIM#203800) is an autosomal recessive rare disorder caused by mutations in ALMS1 (chromosome 2p13), with a frequency estimated at <1:100.000 [1]. The syndrome is multisystemic and major phenotypes include cone-rod retinal dystrophy leading to blindness, hearing loss, obesity, type 2 diabetes mellitus (T2DM), dilated cardiomyopathy, and progressive hepatic and renal failure [1]. Fibrosis in multiple organs has been described [1]. There is considerable variation in the phenotypic spectrum both among and within different families [1, 2].

ALMS1 is ubiquitously expressed, but the function remains unknown. At least one isoform of ALMS1 localizes to the centrosomes and basal bodies of ciliated cells. Studies in murine and cellular models suggest that defects in ciliogenesis and/or structure, function, or maintenance of cilia underlie the pathogenesis of AS [2, 3].

ALMS1 is widely expressed in most regions of the brain (http://www.brain-map.org/). Most AS patients demonstrate normal intelligence, although some reports indicate delayed early psychomotor and intellectual development. Hearing and vision deficits probably contribute to learning delays seen in some young children with AS. Motor milestones are typically delayed by 1–2 years and there may be deficits in coordination, balance, and fine motor skills. A range of autism-spectrum behavior and clonic-tonic or absence-seizure activity has been observed in some cases. Major depression, hyperphagia, obsessive-compulsive, and psychotic behaviors have been noted, particularly in adults [1, 2]. The mechanism underlying the neurological involvement remains unknown in AS and brain imaging has not been studied.

The aim of this study is to specifically investigate central brain involvement by conventional Magnetic Resonance Imaging (MRI), Voxel Based Morphometry (VBM) and diffusion tensor imaging (DTI) in a consistent group of pediatric and adult patients affected by AS.

This study showed that brain involvement is not uncommon in AS patients. On conventional MRI sequences 50% of AS patients presented brain abnormalities including subtle signs of atrophy, periventricular WM abnormalities or lacune-like lesions. Furthermore, VBM revealed white and grey matter volume decrease more evident in the posterior regions while diffusion tensor imaging showed diffuse supratentorial white matter abnormalities involving also the regions that appeared normal on conventional imaging.

So far, neuroimaging data in AS are very scarce. Brain involvement was reported in a 6-year-old girl with AS presenting with aphasia since birth and mild right hemiparesis noted three months before admission [8]. Her brain CT revealed atrophy of the left hemisphere, that according to the authors could have been a coincidental association. Among our patients we had no cases of hemiatrophy, although one patient presented with diffuse mild atrophy and three presented with uni- or bilateral ventricular enlargement without significant increase of subarachnoid spaces. In all cases the ventricular enlargement was more prominent in the posterior part of the lateral ventricles. Likewise, VBM showed a significant white matter and grey matter volume reduction in AS patients, more evident in the posterior cerebral regions.

Although posterior lateral ventricle enlargement has been recognized in several clinical conditions, none of the patients had history of prematurity, peripartum anoxic-ischemic events or head trauma. Interestingly, the posterior horns lie very close to the optic pathway which is primarily affected in AS. A selective atrophy of the optic pathway, therefore, could have contributed to the atrophy of the posterior part of the cerebral hemispheres, as observed in congenital and early blindness [9, 10].

In Bardet Biedl Syndrome (BBS) patients, focal temporal lobe and midline orbitofrontal lobe grey matter volume loss and hippocampal dysplasia were related to a severe and global impact of ciliary dysfunction on forebrain development [11, 12]. Our study disclosed a more diffuse lower grey matter volume without the specific distribution detected in BBS patients. Moreover, no AS patient met the neuroimaging criteria for hippocampal dysplasia. These findings seem to reveal that brain involvement in these two ciliopathies is dissimilar, thus providing some structural basis for the known different cognitive impairment.

Three AS patients presented with periventricular white matter hyperintensity. This type of lesion is frequently observed in normal subjects but at a much older age [13] and is attributed to altered hemodynamics since periventricular area is supplied by noncollateralizing ventriculofugal vessels arising from subependymal arteries. Since up to 60% of AS subjects might present with infant cardiomyopathy and sudden onset of cardiac heart failure in their first month of life [1], parenchymal brain changes might root from heart-related brain hypoxia.

However, cardiac function usually improves before the age of 3, while parenchymal changes seem to appear in AS patients after the age of 30, thus suggesting a different pathogenic mechanism. T2DM, hypercholesterolemia, obesity and heart failure, which are frequent comorbidities in AS, might all contribute to decreased cerebral blood flow, leading to early periventricular white matter hyperintensity in AS patients.

In addition to periventricular white matter lesions, the oldest male patient (43-year-old) had several lesions consistent with small infarcts, almost all in the cerebellar cortex. The pathogenesis of these lesions is unclear. Global hypoperfusion and cardioembolism preferentially involve the supratentorial structures and do not affect almost exclusively the cerebellum as in our patient [14]. On the other hand, bilateral vertebral embolic sources in the young (such as bilateral vertebral artery dissection) do not usually occur without symptoms and would not explain the lesion observed in the left internal carotid artery territory (caudate nucleus). Alternatively, the preferential involvement of the posterior circulation could be related to AS itself. Ciliary involvement in endothelial function has been demonstrated [15].

The presence of primary cilia in arteries with oscillatory flow suggests a region-specific distribution.

These aspects could underlie a region-specific increased susceptibility to risk factors present in AS. Indeed, other inherited conditions (e.g. Fabry disease) present with an increased risk of stroke in the posterior circulation, unveiling a selective vulnerability to metabolic and vascular factors of vertebro-basilar versus carotid territories [16].

Noteworthy, vascular-like lesions in AS patients seem to appear as early as 30 years. Better management of cardiac dysfunction will allow increasing survival of AS patients. The expected wider range of brain involvement will prove or deny the selective vulnerability of the vertebrobasilar territory. Recently, an ischemic stroke in a 21-year-old woman with Joubert syndrome has been reported, suggesting that this condition might be at higher risk for acute brain ischemia [17]. So far, no other ciliopathy has been associated with an increased vulnerability to vascular insults, but studies focused on this topic are lacking.

DTI evaluation added significant and unexpected information on white matter involvement in AS. Diffuse changes in radial diffusivity with almost no change in axial diffusivity were observed both in highly anisotropic regions, where the WM tracts are arranged as compact fiber bundles (e.g. the corpus callosum) and in the less anisotropic regions, where WM tracts are variably intermingled. Similar findings have been reported in other diseases characterized mostly by myelin derangement such as relapsing remitting multiple sclerosis and in animal models of dysmyelination [18]. White matter fractional anisotropy might be significantly and permanently altered by severe infantile myopathy-related hypoxia. However, neonatal hypoxia also alters permanently mean and axial diffusivity [19]. AS patients did not present with mean and axial diffusivity abnormalities (except from the fornix). Moreover, hypoxia usually presents with cerebellar white matter abnormalities [20] that were not found in AS patients.

According to these findings hypoxia does not seem to be able to explain supratentorial white matter changes in AS.

Recently, adolescent patients affected with obesity and metabolic syndrome have been shown to present small white matter clusters of decreased FA suggesting a pathogenic role of diabetes, hypertension and obesity in causing early structural brain changes [21]. These changes were limited (global volume of 4.47 mL), and not comparable with the widespread supratentorial involvement observed in our cohort.

Therefore, our findings uncover a diffuse and symmetric supratentorial myelination abnormality. Intriguingly, primary myelin issues have been already reported in the peripheral nervous system of AS patients. Delamination of the myelin sheaths was detected by transmission electron microscopy at the level of the gingiva [22]. Recently, it has been shown that the primary cilia of Schwann cells are the regulators of Hedgehog signaling-mediated myelination in the peripheral nervous system, [23, 24] while genetic studies have shown that Sonic Hedgehog signaling at the level of primary cilia is essential for patterning the embryonic stem cells into oligodendrocytes [25, 26]. 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. Our findings on AS patients, another ciliopathy that does not feature impairment of cognitive performance, seem to confirm the pivotal role of cilia in the embryogenic mechanism leading to white matter formation.

So far, TBSS has not been applied to investigate white matter changes in BBS, Joubert Syndrome or Meckel-Gruber Syndrome; therefore, it is not possible to clarify whether the white matter involvement observed in AS were a feature shared by other ciliopathies.

The peculiar signal change of the fornix in AS patients is more difficult to unravel. 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. schizophrenia, anorexia nervosa) an involvement of the fornix has been detected. Both these conditions (overweight or obesity and psychiatric disorders) have been observed in AS and might underlie fornix DTI abnormalities. In our group of AS patients ten of twelve were overweight or obese and four had psychiatric issues. On the other hand, the fornix involvement could represent the anatomical substrate leading to weight-related and psychiatry disorders that have already reported in this disease [2].

Finally, AS patients might take several drugs to control comorbidities. Some of these treatments could hypothetically have affected the abovementioned brain MRI findings.

Quetiapine has been shown to determine hippocampal volume loss in schizophrenic patients, [29] while risperidone has been reported to increase frontal lobe intracortical myelin volume as detected by means of inversion recovery and proton density weighted images [30]. In our study group only one patient was treated with the abovementioned drugs: the impact on the statistic should be, therefore, negligible if any.

Two patients received omega-3 fatty acids. Omega-3 fatty acids have been demonstrated to protect against cerobrovascular brain pathology and hippocampal volume loss [31, 32]. Given that VBM data and conventional MRI disclosed mild hippocampal volume loss and increased white matter lesion burden in AS patients compared to age matched controls, a direct effect of omega-3 fatty acids in determining these findings is unlikely.

Alström syndrome patients present with mild brain atrophy and vascular-like lesions at a very young age. Additionally, DTI reveals supratentorial dysmyelination which also entails the white matter that appears normal on conventional MRI sequences. The role of cilia in cerebral parenchymal changes and myelination needs further investigation.

Renzo Manara, Pietro Maffei, Valentina Citton, Bettini Vera, Angela Favaro, Nella Augusta Greggio, Milan Gabriella, Gabrieli Joseph, Jan D Marshall and J K Naggert: These authors should be considered senior co-authors.