Autosomal-Recessive Intellectual Disability with Cerebellar Atrophy Syndrome Caused by Mutation of the Manganese and Zinc Transporter Gene SLC39A8.

Manganese (Mn) and zinc (Zn) are essential divalent cations used by cells as protein cofactors; various human studies and animal models have demonstrated the importance of Mn and Zn for development. Here we describe an autosomal-recessive disorder in six individuals from the Hutterite community and in an unrelated Egyptian sibpair; the disorder is characterized by intellectual disability, developmental delay, hypotonia, strabismus, cerebellar atrophy, and variable short stature. Exome sequencing in one affected Hutterite individual and the Egyptian family identified the same homozygous variant, c.112G>C (p.Gly38Arg), affecting a conserved residue of SLC39A8. The affected Hutterite and Egyptian individuals did not share an extended common haplotype, suggesting that the mutation arose independently. SLC39A8 is a member of the solute carrier gene family known to import Mn, Zn, and other divalent cations across the plasma membrane. Evaluation of these two metal ions in the affected individuals revealed variably low levels of Mn and Zn in blood and elevated levels in urine, indicating renal wasting. Our findings identify a human Mn and Zn transporter deficiency syndrome linked to SLC39A8, providing insight into the roles of Mn and Zn homeostasis in human health and development.

Evidence for cerebellar dysfunction in Chinese children with developmental dyslexia: an fMRI study.

Numerous studies reported that developmental dyslexia in alphabetic languages was associated with a wide range of sensorimotor deficits, including balance, motor skill and time estimation, explained by skill automatization deficit hypothesis. Neural correlates of skill automatization deficit point to cerebellar dysfunction. Recently, a behavioral study revealed an implicit motor learning deficit in Chinese children with developmental dyslexia in their left hands, indicating left cerebellar dysfunction. Using functional magnetic resonance imaging (fMRI), our study examined the brain activation during implicit motor learning in 9 Chinese dyslexic and 12 age-matched children. Dyslexic children showed abnormal activations in the left cerebellum, left middle/medial temporal lobe and right thalamus compared with age-matched children during implicit motor learning. These findings provide evidence of cerebellar abnormality in Chinese dyslexic people. Furthermore, dysfunction of the left cerebellum in Chinese dyslexia is inconsistent with the right cerebellum abnormalities that were reported by studies on alphabetic-language dyslexia, suggesting that neurobiological abnormalities of impaired reading are probably language specific.

Molecular characterization of Joubert syndrome in Saudi Arabia.

Joubert syndrome (JS) is a ciliopathy that is defined primarily by typical cerebellar structural and ocular motility defects. The genetic heterogeneity of this condition is significant with 16 genes identified to date. We have used a combination of autozygome-guided candidate gene mutation analysis and exome sequencing to identify the causative mutation in a series of 12 families. The autozygome approach identified mutations in RPGRIP1L, AHI1, TMEM237, and CEP290, while exome sequencing revealed families with truncating mutations in TCTN1 and C5ORF42. Our study, the largest comprehensive molecular series on JS, provides independent confirmation of the recently reported TCTN1, TMEM237, and C5ORF42 as bona fide JS disease genes, and expands the allelic heterogeneity of this disease.

A dominantly inherited progressive disease in a black family characterised by cerebellar and retinal degeneration, external ophthalmoplegia and abnormal mitochondria.

A report is given of a black family with a dominantly inherited, neuro-retinal degeneration associated with abnormally large mitochondria, in which the cristae are disoriented. The disease is characterised by progressive external ophthalmoplegia, clear-cut macular degeneration, cerebellar dysarthria, spastic paraplegia and finally facial and bulbar weakness. A similar illness has been described in black families and individuals and we suggest that the disease may represent a specific syndrome, possibly confined to blacks, that lies within the spectrum of the so-called mitochondrionopathies.