Warburg Micro Syndrome 1

A number sign (#) is used with this entry because Warburg Micro syndrome-1 (WARBM1) is caused by homozygous mutation in the RAB3GAP1 gene (602536) on chromosome 2q21.

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).

Genetic Heterogeneity of Warburg Micro Syndrome

Warburg Micro syndrome-2 (WARBM2; 614225) is caused by mutation in the RAB3GAP2 gene (609275) on chromosome 1q41. WARBM3 (614222) is caused by mutation in the RAB18 gene (602207) on chromosome 10p12. WARBM4 (615663) is caused by mutation in the TBC1D20 gene (611663) on chromosome 20p13.

See also Martsolf syndrome (212720), a clinically overlapping but milder autosomal recessive disorder caused by autosomal recessive mutation in the RAB3GAP2 gene.

Handley et al. (2013) provided an overview of the disease variants identified in the RAB3GAP1, RAB3GAP2, and RAB18 genes, noting that a total of 144 families with WARBM and 9 families with Martsolf syndrome had been studied. Mutations were identified in RAB3GAP1 in 41% of cases, in RAB3GAP2 in 7% of cases, and in RAB18 in 5% of cases. Although RAB18 had not been linked to RAB3 pathways, Handley et al. (2013) stated that mutations in all 3 genes cause an indistinguishable phenotype, making it likely that there is some functional overlap.

Clinical Features

Warburg et al. (1993) used the designation Micro syndrome for an autosomal recessive syndrome comprising microcephaly, microcornea, congenital cataract, mental retardation, optic atrophy, and hypogenitalism. They described an affected brother and sister and their male cousin. The sibs were offspring of a consanguineous Pakistani marriage; the parents of the cousin denied consanguinity. Agenesis of the corpus callosum, prominent root of the nose, large anteverted ears, facial hypertrichosis, small pupils with posterior synechiae, hypotonia, mild to moderate spastic palsy with hip dislocations, and hormonal dysfunction, presumably of hypothalamic origin, were other features. The children were almost blind, whether or not the cataracts had been operated on. The electroretinographic responses indicated dysfunction of both retinal rods and cones, and the visual evoked potentials confirmed optic nerve atrophy. The children were late walkers and were incontinent of urine and stools. In the differential diagnosis, Warburg et al. (1993) considered COFS syndrome (214150), CAMAK/CAMFAK syndromes (212540), Martsolf syndrome (212720), lethal Rutledge syndrome (270400), and lethal Neu-Laxova syndrome (256520).

Cases similar in nature to the phenotype designated 'Micro syndrome' by Warburg et al. (1993) had previously been described. Sjogren and Larsson (1949) reported 5 unrelated patients, 2 males and 3 females, with microphthalmia, mental retardation, and spastic diplegia. Additional ocular features included cataract in 2 patients, retino-choroiditis in 1, and degeneration of the retina in 1. Three of the patients also had epilepsy.

Pinsky et al. (1965) described 3 sisters with microcephaly, microphthalmia, corneal opacity, severe mental retardation, spastic cerebral palsy, and seizures. None had cataract or coloboma, although 2 had pupillary abnormalities. Their mother had unilateral microphthalmia and was of normal intelligence.

Balci et al. (1974) reported a 2-year-old girl, born of first-cousin parents, who had microcephaly, microphthalmia, diffuse corneal opacity, mental retardation, generalized muscular spasticity, and seizures. Urine chromatograms indicated significant glycinuria and a large glycine spot was detected by blood analysis.

Seemanova and Lesny (1996) described a 6-year-old Czech boy who had microcephaly, microphthalmia, microcornea, congenital cataract, severe mental deficiency, progressive spastic diplegia, hypogenitalism, and growth retardation. Dysmorphic features included brachycephaly, upslanting palpebral fissures, epicanthal folds, highly arched palate, small mouth, and retrognathia. At 6 years of age, the proband was unable to sit, walk, or speak. He had a similarly affected maternal uncle, and 2 maternal male cousins may also have been affected. Chromosomal and metabolic findings in the proband were normal. Seemanova and Lesny (1996) noted that the features in these patients resembled those of several autosomal recessive disorders, including Martsolf syndrome, but considered the phenotype distinct because of probable X-linked inheritance.

Megarbane et al. (1999) reported 4 children from a highly inbred Shiite Muslim family from southern Lebanon with hypotonia, spastic diplegia, microcephaly, microphthalmia, congenital cataract, optic atrophy, ptosis, kyphoscoliosis, short stature, severe mental retardation, and cerebral malformations. Six other children in the kindred were probably also affected. Megarbane et al. (1999) considered a number of possible diagnoses, but thought that the phenotype of this family most closely resembled that of Warburg Micro syndrome.

Rodriguez Criado et al. (1999) reported 2 sisters, born to unrelated parents, who displayed microcephaly, microphthalmia, microcorneas, cataracts, sparse medial eyebrows, micrognathia, and severe psychomotor retardation. Cerebral MRI in both showed subcortical atrophy with large ventricles, bilateral frontoparietal and insula cortical dysplasia, and hypoplasia of the corpus callosum and the vermis with a large cisterna magna. At 14 and 4 years of age, respectively, neither girl could speak or stand, and neither had sphincter control. Rodriguez Criado et al. (1999) noted that their patients had features similar to those originally described by Warburg et al. (1993) but had a different facial dysmorphism.

Ainsworth et al. (2001) studied 14 children with Micro syndrome, all from consanguineous families, and identified several consistent ophthalmic findings that they proposed might be pathognomonic for the syndrome: microphthalmos, microphakia, cataract, atonic pupils, mild optic atrophy, and severe cortical vision impairment. In addition, they noted that all of their patients had marked microcephaly within the first few months of life, hypotonia, spasticity within the first year of life, and severe global developmental delay. MRI revealed variable development of the corpus callosum, ranging from marked hypogenesis to normal in 1 patient; all images demonstrated some degree of pachygyria. Only some of the patients displayed the subtle dysmorphic facial features described by Warburg et al. (1993).

Derbent et al. (2004) reported a 7-month-old male, born to first-cousin Turkish parents, who had bilateral lens opacity and unresponsive pupils, low-set and posteriorly angulated ears, broad nasal root and beaked nose, long philtrum, micrognathia, and high-arched palate. He also had bilateral cryptorchidism and micropenis, mental delay, truncal hypotonia, and increased muscle tone in both legs. MRI revealed hypoplasia of the corpus callosum, diffuse cortical and subcortical atrophy, reduced myelinization, enlarged cisterna magna, and small orbits. An unusual finding in this patient was fusion of the lower poles of the kidneys and an ectopic left kidney.

Graham et al. (2004) described 3 pairs of affected sibs, including 1 pair with consanguineous parents, who were born with microcephaly, microcornea, and cataracts.

Abdel-Salam et al. (2007) described 7 Egyptian patients (5 males and 2 females) from 5 families with microcephaly, mild microphthalmia, microcornea, congenital cataracts, and hypogenitalism (only in males). Facial features were consistent with those originally described in the Micro syndrome in 3 patients; the remainder of the patients had facies similar to those described in Martsolf syndrome. The patients had a variable degree of brain atrophy, but hypogenesis of the corpus callosum was evident only in 5 patients. Abnormal gyral pattern, small cerebellum, vermian hypoplasia, and delayed myelination were additional imaging findings in 3 cases. All patients had delayed visual evoked potential but normal electroretinogram.

Yuksel et al. (2007) reported a 4-year-old boy with Warburg Micro syndrome, the offspring of first-cousin Turkish parents, who had the additional features of skin hyperextensibility, joint hypermobility, deformities of metatarsals in both feet, and overlapping toes.

Morris-Rosendahl et al. (2010) studied 7 patients with Warburg Micro syndrome from 5 families, all of whom had homozygous RAB3GAP1 (602536) mutations. Features that were consistently found in these patients included postnatal microcephaly, microphthalmia, microcornea, bilateral congenital cataracts, short palpebral fissures, optic atrophy, severe mental retardation, and congenital hypotonia with subsequent spasticity. Only 1 patient had microcephaly at birth. Analysis of brain MRIs revealed a consistent pattern of polymicrogyria in the frontal and parietal lobes, wide sylvian fissures, a thin hypoplastic corpus callosum, and increased subdural spaces.

Diagnosis

Graham et al. (2004) pointed out that a prenatal viral infection should be ruled out before considering mendelian origins for Micro syndrome. Nucleotide excision repair (NER) studies in cultured fibroblasts can be used to distinguish patients with Micro syndrome from those with COFS syndrome or Cockayne syndrome (see 216400), because the latter demonstrate hypersensitivity to ultraviolet radiation, whereas patients with Micro syndrome have normal results. Graham et al. (2004) stated that Micro syndrome can be distinguished from other similar clinical disorders with normal NER by the presence of significant visual impairment and cortical blindness despite early surgery for congenital cataracts, frontal polymicrogyria, thin corpus callosum, and cortical atrophy on MRI.

Mapping

Aligianis et al. (2005) carried out a 10-cM genomewide scan in 12 individuals with Warburg Micro syndrome from 8 consanguineous kindreds (7 Pakistani and 1 Moroccan), 5 of which had previously been described by Ainsworth et al. (2001). All affected individuals from 5 families were homozygous with respect to markers D2S410 and D2S1399. Genotyping of additional microsatellite markers in family members of these 5 kindreds confirmed a region of homozygosity at chromosome 2q21.3.

Molecular Genetics

Aligianis et al. (2005) identified inactivating mutations in the RAB3GAP1 gene (e.g., 602536.0001) in 5 kindreds with Warburg Micro syndrome linked to chromosome 2q21.3, 2 of which had previously been described by Ainsworth et al. (2001), but not in 3 unlinked kindreds. Investigation of an additional 10 families with Warburg Micro syndrome identified germline inactivating mutations in 7 families, including the family in which Warburg Micro syndrome was first described (Warburg et al., 1993) and 2 other families previously reported by Megarbane et al. (1999) and Graham et al. (2004), respectively. Kindreds with or without mutations in RAB3GAP1 were clinically indistinguishable.

Abdel-Salam et al. (2007) performed linkage analysis using markers flanking the RAB3GAP1 and RAB3GAP2 genes in 2 unrelated Egyptian patients with clinical features of Micro syndrome and found homozygosity for all markers flanking RAB3GAP1 in a 2-year-old boy, in whom they identified an R671X mutation (602536.0004) in the RAB3GAP1 gene. The other patient, an 11-month-old girl with an affected older brother who died at 2.5 years of age, showed no evidence of linkage to either gene.

In 7 patients with Warburg Micro syndrome from 5 families with Turkish, Palestinian, Danish, and Guatemalan backgrounds, Morris-Rosendahl et al. (2010) identified homozygosity for 5 different truncating RAB3GAP1 mutations, respectively (see, e.g., 602536.0006 and 602536.0007).

Handley et al. (2013) screened the RAB3GAP1, RAB3GAP2, and RAB18 genes in patients diagnosed with WARBM or Martsolf syndrome and identified homozygosity or compound heterozygosity for mutations in RAB3GAP1 (e.g., 602536.0003 and 602536.0008-602536.0011) in patients from 42 families, including the Czech boy with features of WARBM who was originally described by Seemanova and Lesny (1996). Handley et al. (2013) noted that 2 of the variants were missense mutations: homozygosity for T18P (602536.0010) was identified in affected children from 5 unrelated families of various ethnic origins, and for E24V (602536.0011) in an Egyptian family. Both missense mutations occurred at highly conserved residues, segregated with disease in each family, and were not found in 270 control chromosomes. The affected children all had typical eye, brain, and genital findings that were consistent with a diagnosis of WARBM.