Review 1608178 Eur J Hum Genet 1995;3:273-284 Erik Fransen3' CRASH Syndrome: Clinical Spectrum Vance Lemmon0 Guy Van Campa of Corpus Callosum Hypoplasia, Lieve Vitsa Retardation, Adducted Thumbs, Paul Couckea Patrick J. Willemsa Spastic Paraparesis and a Department of Medical Genetics, Hydrocephalus Due to Mutations in University of Antwerp, Belgium; One Single Gene, L1 b Case Western Reserve University, Cleveland, Ohio, USA Keywords Abstract X-linked disorder LI is a neuronal cell adhesion molecule with important func­ Mental retardation tions in the development of the nervous system. The gene Hydrocephalus encoding LI is located near the telomere of the long arm of the MASA syndrome X chromosome in Xq28. We review here the evidence that Adducted thumbs several X-linked mental retardation syndromes including X- Corpus callosum agenesis linked hydrocephalus (HSAS), MASA syndrome, X-linked Spastic paraplegia complicated spastic paraparesis (SPI) and X-linked corpus LI callosum agenesis (ACC) are all due to mutations in the LI CRASH gene. The inter- and intrafamilial variability in families with Mutation analysis an LI mutation is very wide, and patients with HSAS, MASA, SPI and ACC can be present within the same family. There­ fore, we propose here to refer to this clinical syndrome with the acronym CRASH, for Corpus callosum hypoplasia, Retar­ dation, Adducted thumbs, Spastic paraplegia and Hydroceph­ alus. Clinical Aspects for Hydrocephalus due to Stenosis of the Aqueduct of Sylvius. This designation was X-Linked Hydrocephalus based upon the presence of aqueductal steno­ X-linked hydrocephalus (MIM No. sis in many HSAS patients [1]. However, later 307000) was originally described by Bickers studies reported several HSAS patients with and Adams in 1949. It is referred to as HSAS hydrocephalus but without aqueductal steno- Received: April 21,1995 Patrick Willems © 1995 Revision received: July 28,1995 Department of Medical Genetics S. Karger AG, Basel Accepted: August 4, 1995 University of Antwerp B-2610 Antwerp (Belgium) sis [2]. Therefore, the occurrence of aqueduc- reported, and some families have been rede­ tal stenosis in X-linked hydrocephalus might fined as representative of the MASA syn­ not be the cause of hydrocephalus. Neverthe­ drome [9-17], The clinical features show in­ less, the designation of HSAS is still used in ter- and intrafamilial variation, with mental the literature. HSAS is the most common retardation being the only obligatory symp­ genetic cause of hydrocephalus with an inci­ tom. Although MASA syndrome is an X- dence of approximately 1/30,000 male births, linked recessive condition, some expressing and it is responsible for about one quarter of carrier females have been reported, possibly male patients with hydrocephalus not associ­ due to unfavorable lyonization of the wild- ated with spina bifida [3]. The clinical spec­ type gene [9,14], Corpus callosum agenesis or trum of HSAS is very broad and shows great dysgenesis is also a frequent symptom in intra- and interfamilial variation. The only MASA patients [15]. Even though earlier obligate feature is mental retardation, with studies [9] noticed the clinical overlap be­ IQs usually ranging between 20 and 50. Hy­ tween MASA and HSAS, a clear distinction drocephalus presents from impressive macro- was made between those two conditions, cephaly, resulting in pre- or perinatal death, to based upon the presence or absence of hydro­ minimal enlargement of the ventricles. More­ cephalus in HSAS and MASA, respectively. over, HSAS families have been described in However, in later clinical studies, the sharp which some mentally retarded members did boundaries between HSAS and MASA be­ not have hydrocephalus [4, 5]. Adducted gan to fade away as (1) HSAS families were thumbs are seen in approximately 90% of the reported in which some affected members cases. Other features are spastic paraplegia, did not have hydrocephalus [4, 5], (2) some nystagmus and structural brain defects such MASA families contained HSAS patients as hypoplasia of the corpus callosum and sep­ with hydrocephalus [16], and (3) linkage stud­ tum pellucidum [5], HSAS is a recessive X- ies assigned the MASA disease locus to Xq28, linked disorder with no symptoms in carrier the same region as HSAS [16, 17]. This led us females. In 1990, we assigned the HSAS dis­ to suggest that HSAS and MASA were allelic ease locus to the distal part of the long arm of disorders due to mutations in the same gene the X chromosome in Xq28 by linkage analy­ [6]. sis [6], Further mapping studies refined the disease locus to a region of 2 Mb, distal to Spastic Paraplegia DXS52 and proximal to F8C [7, 8]. As the Spastic Paraplegia (SP) is a clinically and neural cell adhesion molecule LI (LICAM) is genetically heterogeneous condition. Some in­ located in this interval, we suggested that vestigators divide SP into pure and compli­ HSAS might be due to mutations in LI [7], cated forms [18], In pure SP, spasticity of the lower extremities is the only clinical sign. In MASA Syndrome complicated SP, additional symptoms such as In 1974, Bianchine and Lewis described an mental retardation and/or congenital brain X-linked disorder characterized by Mental re­ malformations are present. Most hereditary tardation, aphasia, .Shuffling gait and Ad­ forms of SP are inherited in an autosomal ducted thumbs [9], Referring to these four dominant or recessive way, whereas X-linked clinical features, the name ‘MASA syndrome’ SP is rare. A locus for X-linked SP (SP2) has was assigned to this disease (MIM No. been localized on the long arm of the X chro­ 303350). Several MASA families have been mosome in Xq21-q22, both in families with 274 Fransen/Lemmon/V an Camp/Vits/ CRASH Syndrome Coucke/WiUems pure [19] and complicated [20] SP. This lat­ linked recessive condition with ACC and a ter form of SP results from mutations in the variety of symptoms including macrocephaly, proteolipid protein (PLP) gene and is allelic anal anomalies, Hirschsprung’s disease, con­ to Pelizaeus-Merzbacher disease (MIM No. stipation, hypotonia and mental retardation 312080), a severe X-linked disorder in which [22], The gene responsible for FG syndrome progressive demyelination of the central ner­ has been mapped to Xql 3 [Briault, pers. com­ vous system occurs [21], Kenwrick et al. [12] mun.]. Several ACC/DCC syndromes with have described a form of X-linked compli­ unknown sublocalization on the X chromo­ cated SP (SPI, MIM No. 312900) in a family some have been described. Menkes et al. [23] with SP, mental retardation and adducted have reported a family with X-linked ACC/ thumbs. Linkage analysis assigned the SPI DCC, seizures, mental retardation and disease locus to the distal part of the long arm Hirschsprung’s disease, which might repre­ of the X chromosome in Xq28. Later clinical sent an example of FG syndrome. An X- studies of this SPI family revealed that the linked DCC family with hydrocephalus, mi­ clinical spectrum was compatible with MASA crocephaly, mental retardation and brachy- syndrome [17], suggesting that SPI and dactyly has been reported by Kang et al. [24], MASA syndrome are coallelic. Kaplan [25] reported two males with com­ plete absence of the corpus callosum and Agenesis of the Corpus Callosum severe psychomotor retardation, one of the The corpus callosum is the largest fiber patients having adducted thumbs and slightly tract in the brain, and plays a key role in the enlarged ventricles. This spectrum of anoma­ communication between the two brain hemi­ lies is reminiscent of MASA syndrome. The spheres. Corpus callosum agenesis (ACC) or fact that ACC/DCC in some families might dysgenesis (DCC) is a rather aspecific abnor­ represent MASA, is also corroborated by the mality. Many cases of DCC, and to a lesser finding that ACC or DCC have been reported extent ACC, are found incidentally at necrop­ in patients with MASA syndrome [15] and sy in individuals who had normal cerebral HSAS [5]. This suggests that there might be function. The frequency of ACC/DCC in the just one gene for HSAS, MASA, SPI and general population has been estimated at 0.3- ACC/DCC. 0.7%, whereas it is found in 2-3% of the men­ tally retarded. In most cases, ACC/DCC is an isolated finding. However, ACC and DCC Molecular Aspects can also occur as part of a syndrome, when accompanied by a number of other malforma­ Identification of LI as the tions. Many chromosomal and monogenic Disease-Causing Gene in HSAS, MASA, disorders have ACC/DCC in their spectrum SPI and ACC/DCC of anomalies. X-linked forms of ACC/DCC, The localization of the HSAS gene in Xq28 however, are very rare. Aicardi syndrome, an in a 2-Mb interval containing the LI X-linked disorder that occurs only in females, (LICAM) gene suggested that LI was a candi­ has a clinical spectrum including ACC, cho­ date gene for HSAS [7], Therefore, extensive rioretinal lacunae, infantile spasms and psy­ mutation analysis was performed in the LI chomotor retardation. The gene involved in gene from a large number of HSAS families. Aicardi syndrome has provisionally been In 1992, the first LI mutation in an HSAS mapped to Xp22. FG syndrome is an X- family was reported by Rosenthal et al. [26]. 275 Table 1. LI mutations in HSAS, MASA, SPI and ACC families No. Mutation Exon Domain Disease Ref­ cDNA level protein level erence 1 321 Del 80 FS 107 frameshift 4 Ig2 HSAS 29 2 G551A R184Q missense 6 Ig2 HSAS 30 3 C630G H210Q missense 6 Ig2 M ASA/ACC 32 4 G791T C264Y missense 7 Ig3 HSAS 28 5 G1354A G452R missense 11 Ig5 HSAS 30 6 C1453T R485STOP nonsense 12 Ig5 HSAS 30 7 G1792A D598N missense 14 Ig6 MASA 32 8 2137 Ins 39 8121ns 13AA insertion intron 17 Fn2 HSAS 26 9 2884 Del G FS 961 frameshift 22 Fn4 HSAS 30 10 3489 Del TG FS 1163 frameshift 26 cytoplasmic SPI 30 11 C3581T S1194L missense 28 cytoplasmic MASA 31 12 3541 Dpi 125 FS 1223 frameshift 28 cytoplasmic HSAS 27 13 Del 3541-end FS1181 frameshift 26-28 cytoplasmic MASA 32 This was a novel mutation in a branch point LI Protein and Function signal of an intron, leading to aberrant splic­ LI, also referred to as LI CAM, is a neuro­ ing.