X‐linked mental retardation and/or hydrocephalus

Abstract

A family in which a brother and 5 sons of five sisters were mentally retarded without major physical abnormality, is reported. Two hydrocephalic males also occurred in the family. The possibility is entertained that in this family (and probably in others) an X‐linked gene caused either non‐specific mental retardation or hydrocephalus associated with mental retardation. Some minor physical and neurological abnormalities were found in some of the affected males, and their intelligence varied considerably within the retarded range.

Mutations in the AP1S2 gene encoding the sigma 2 subunit of the adaptor protein 1 complex are associated with syndromic X-linked mental retardation with hydrocephalus and calcifications in basal ganglia

“…Within this large interval, >70 characterised genes and expressed sequence tag (EST) clusters have been identified. In this paper, we report the description of a second family with clinical features reminiscent of those reported by Fried6 7 and the results of linkage studies refining the localisation of the gene in Xp22. We also report the results of sequencing of candidate genes located in this interval and the involvement of the AP1S2 gene recently found mutated in XLMR in the Fried syndrome 8…”

“…However, several examples of families with HSAS suggest a genetic heterogeneity in this disease 4 5. Over 34 years ago, Fried described a Scottish family with X-linked mental retardation (XLMR) associated with hydrocephalus or calcifications in the basal ganglia, or both 6 7. The family included six male patients with mental retardations in two generations.…”

Infantile hydrocephalus: A review of epidemiology, classification and causes

“…Fried syndrome, first described in 1972 [32], was once thought to be an example of L1 syndrome before it was recognized as a separate X-linked disorder [33]. Now known to be caused by mutations in the AP1S2 gene [34], Fried syndrome is characterized primarily by intellectual disability with prominent basal ganglia iron deposition or calcifications [35] on CT scan (which may not be obvious on MRI), and variable hydrocephalus.…”

“…Mutations in the same gene have now been recognized as the cause of other overlapping X-linked intellectual disability syndromes [35] that are often accompanied by hydrocephalus. The severity and radiographic appearance of the hydrocephalus associated with mutations in AP1S2 has not been well characterized, but has been described as aqueductal stenosis in at least some affected individuals [32], though others may have retrocerebellar or 4 th ventricular (Dandy-Walker spectrum) cysts [35]. We recommend considering AP1S2 testing in males with intellectual disability and imaging abnormalities that suggest deposition of iron or calcium with the basal ganglia.…”

Clinical, cellular, and neuropathological consequences ofAP1S2mutations: further delineation of a recognizable X-linked mental retardation syndrome

“…Affected males had mild-to-profound MR, hypotonia early in life, delayed walking, speech delay, and aggressive behavior [Carpenter et al, 1999;Turner et al, 2003;Tarpey et al, 2006;Saillour et al, 2007]. Interestingly, patients from 1 of the 5 families had been diagnosed with Fried syndrome, a distinct XLMR syndrome further characterized by basal ganglia calcifications, hydrocephalus, and spasticity [Fried, 1972;Strain et al, 1997;Saillour et al, 2007].…”