Warburg Micro Syndrome 3

A number sign (#) is used with this entry because of evidence that Warburg Micro syndrome-3 (WARBM3) is caused by homozygous or compound heterozygous mutation in the RAB18 gene (602207) on chromosome 10p12.

Description

Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (summary by Morris-Rosendahl et al., 2010).

For a discussion of genetic heterogeneity of Warburg Micro syndrome, see 600118.

Clinical Features

Graham et al. (2004) described a Caucasian sister and brother who had microcephaly, postnatal growth retardation, cataract, microcornea, atonic pupils, optic atrophy, profound mental retardation, hypotonic spastic diplegia, polymicrogyria, hypoplasia of the corpus callosum, and hypogenitalism. A nerve conduction study in the boy was markedly abnormal due to severe loss of neurons, suggesting an axonal peripheral neuropathy.

Bem et al. (2011) studied 6 consanguineous families segregating Warburg Micro syndrome, including 4 Pakistani families originally described by Ainsworth et al. (2001), 1 Caucasian family originally reported by Graham et al. (2004), and 1 Turkish family. All of the affected children had microcephaly, brachycephaly, microphthalmia, microcornea, low anterior hairline, large protruding pinnae, and downturned mouth corners. The older children were wheelchair bound and had kyphoscoliosis, severe spastic quadriplegia with contractures, and diminished muscle bulk. The clinical features were indistinguishable from those in patients with WARBM1 (600118) with RAB3GAP1 (602356) mutations and from those in patients with WARBM2 (614225) with RAB3GAP2 (609275) mutations, but mutations in these genes were excluded by linkage and direct sequencing.

Handley et al. (2013) studied a 4-year-old Egyptian girl who had postnatal growth retardation and microcephaly, bilateral cataracts, microphthalmia, microcornea, atonic pupils, optic nerve atrophy, profound mental retardation with no words or signs, axial hypotonia, hypotonic upper limbs, hypertonic lower limbs with contractures, myoclonic seizures, and hypoplastic labia minora and clitoral hypoplasia. MRI showed bilateral frontoparietal polymicrogyria extending to the insula and temporal gyri, cortical atrophy, delayed myelinization, hypoplasia of the cerebellar vermis and corpus callosum, and mild ventriculomegaly.

Mapping

Bem et al. (2011) performed a genomewide linkage scan in 5 large consanguineous families segregating Warburg Micro syndrome and genotyped 11 affected children and 4 unaffected sibs. In all affected children, a 10,113.089-kb region of shared homozygosity was identified on chromosome 10p12.1. The genotyping was consistent with linkage; the parents were heterozygous and the unaffected sibs had a haplotype different from that of their affected sibs. A maximum 2-point lod score of 8.93 (theta = 0 at D10S1749) was calculated on the assembled haplotypes.

Molecular Genetics

In affected members of 5 large consanguineous kindreds segregating Warburg Micro syndrome, including 4 Pakistani families originally described by Ainsworth et al. (2001) and 1 Turkish family, Bem et al. (2011) identified homozygous loss-of-function mutations in the RAB18 gene (602207.0001 and 602207.0002, respectively). The mutation in the Pakistani families was a founder mutation. Direct sequencing for RAB18 mutations in 58 additional families segregating Warburg Micro syndrome detected compound heterozygous mutations (602207.0003-602207.0004) in the affected sibs previously described by Graham et al. (2004). Bem et al. (2011) performed nucleotide-binding assays and showed that although RAB18 bound GDP and GTP comparably to other RABs (RAB5A, 179512; RAB35, 604199), the RAB18 L24Q (602207.0001) and R93del (602207.0003) mutant proteins did not bind detectable levels of either GDP or GTP and are therefore functionally null. Bem et al. (2011) noted that the pathogenicity of these mutations could be explained by their lack of guanosine nucleotide binding because, as for other RAB proteins, this is a prerequisite for correct subcellular localization and function.

In a 4-year-old Egyptian girl with 'classic' Warburg Micro syndrome, Handley et al. (2013) identified homozygosity for a missense mutation in the RAB18 gene (T95R; 602207.0005).