Galloway-Mowat Syndrome 1

A number sign (#) is used with this entry because of evidence that Galloway-Mowat syndrome-1 (GAMOS1) is caused by homozygous mutation in the WDR73 gene (616144) on chromosome 15q25.

Description

Galloway-Mowat syndrome is a rare autosomal recessive neurodegenerative disorder characterized by infantile onset of microcephaly and central nervous system abnormalities resulting in severely delayed psychomotor development. Brain imaging shows cerebellar atrophy and sometimes cerebral atrophy. More variable features include optic atrophy, movement disorders, seizures, and nephrotic syndrome (summary by Vodopiutz et al., 2015).

Genetic Heterogeneity of Galloway-Mowat Syndrome

See also GAMOS2 (301006), caused by mutation in the LAGE3 gene (300060) on chromosome Xq28; GAMOS3 (617729), caused by mutation in the OSGEP gene (610107) on chromosome 14q11; GAMOS4 (617730), caused by mutation in the TP53RK gene (608679) on chromosome 20q13; GAMOS5 (617731), caused by mutation in the TPRKB gene (608680) on chromosome 2p13; GAMOS6 (618347), caused by mutation in the WDR4 gene (605924) on chromosome 21q22; GAMOS7 (618348), caused by mutation in the NUP107 gene (607617) on chromosome 12q15; and GAMOS8 (618349), caused by mutation in the NUP133 gene (607613) on chromosome 1q42.

Clinical Features

Galloway and Mowat (1968) observed a brother and sister with microcephaly, hiatus hernia, and nephrotic syndrome. The sibs died from nephrosis at ages 20 and 28 months. Parental consanguinity could not be demonstrated.

Shapiro et al. (1976) studied a family with affected brother and sister. The parents were unrelated and of different ethnic extraction. The ears were large and floppy. Albuminuria was present from birth. Microcystic dysplasia and focal glomerulosclerosis were found at autopsy. The hiatus hernia caused vomiting with the first oral feeding. The girl had failure of cleavage of the anterior chambers of both eyes. The sibs died at 14 days and 3 years of age, respectively.

Roos et al. (1987) found reports of 12 cases and described 2 affected sons of nonconsanguineous parents.

Cooperstone et al. (1993) described 3 additional patients, of whom 2 were brother and sister, and reviewed 16 reported cases. Every patient but one had died before age 5.5 years. This was probably the disorder described by Palm et al. (1986) in 2 male sibs (a boy aged 2 years 10 months at death and a male fetus aborted at 22 weeks of gestation). They had similar brain and kidney malformations, namely, paraventricular heterotopias, central canal abnormalities (including hydrocephalus due to aqueductal stenosis in the boy), and glomerular kidney disease with proteinuria. In the fetus the central canal of the spinal cord was represented by 2 or 3 separate tubes. The kidneys were of normal gross appearance but histologically showed several small cysts lying mainly at the corticomedullary junction, lined with rather high epithelium and containing eosinophilic fluid. The authors pointed to a report of a single case of nephrosis and abnormal neuronal migration (Robain and Deonna, 1983). The patient was female.

Garty et al. (1994) described a family of Jewish North African origin in which 2 males and a female out of 8 sibs from an uncle-niece marriage had congenital nephrotic syndrome due to diffuse mesangial sclerosis, microcephaly, and psychomotor retardation. The kidneys showed deposits of IgG and C3 in the mesangium and glomerular basement membranes. All 3 children died before the age of 3 years. Garty et al. (1994) reported that of 19 published cases of children with congenital nephrotic syndrome and microcephaly, only 4 had histologic evidence of diffuse mesangial sclerosis and 2 of their sibs probably had the same disease.

Hou and Wang (1995) described the cases of 2 unrelated Chinese female infants with microcephaly, apparent porencephaly or encephalomalacia, developmental delay, minor facial anomalies, and contractural arachnodactyly. In 1 patient, focal glomerulosclerosis was diagnosed histologically by percutaneous renal biopsy performed to investigate the proteinuria with hematuria. Congenital hypothyroidism, presenting with markedly low T3 and T4, was also present in this patient, who died at age 5 months. The second patient had a similar condition but less severe brain and kidney malformations.

Kingo et al. (1997) described an infant with presumed Galloway-Mowat syndrome who died at the age of 32 days. The diagnosis was made on the basis of microcephaly, congenital nephrosis, and hiatus hernia. Most of the findings had previously been described in this syndrome; thyroid dysplasia and adrenal hypoplasia were found and considered likely components of the syndrome.

Colin et al. (2014) reported 3 patients from 2 unrelated families with GAMOS. Two Moroccan sibs presented with progressive postnatal secondary microcephaly (-2.5 to -3 SD in the first years of life), peripheral and axial hypotonia, severe intellectual disability, and seizures; one also had nystagmus. An unrelated boy, born of consanguineous Turkish parents, had microcephaly, hypertonia, intellectual disability, and spasticity. All patients also had optic atrophy and facial dysmorphism. Brain imaging of all 3 children showed severe cerebellar atrophy, thin corpus callosum, and cortical atrophy. No apparent myelin or gyration defects were observed. Two of the unrelated patients developed nephrotic syndrome at ages 5 and 8 years, respectively; the third patient, who was a sib, had normal renal function and no proteinuria at age 7. One patient with nephrotic syndrome developed chronic renal insufficiency and died at age 5 years. Renal biopsy showed severe collapsing focal segmental glomerulosclerosis and hypertrophic podocytes, as well as interstitial fibrosis and tubular dilations. The other patient with nephrotic syndrome had normal renal function with no proteinuria at age 13 years, but renal biopsy showed mild focal segmental glomerulosclerosis, hypertrophic podocytes, and some tubulointerstitial lesions.

Ben-Omran et al. (2015) reported 2 sisters, born of consanguineous Egyptian parents, with GAMOS. They presented in infancy with severe global developmental delay, intellectual disability with lack of speech, mild microcephaly, axial hypotonia and inability to walk, and spastic quadriplegia with limited joint mobility and talipes foot deformities. Dysmorphic facial features included hypertelorism, epicanthal folds, large nose with prominent nasal bridge and tip, wide mouth, and strabismus. Both girls had biochemical features consistent with nephrotic syndrome. Brain imaging showed ventricular dilatation, small brainstem, thin corpus callosum, delayed myelination, and cerebellar hypoplasia reminiscent of a Dandy-Walker malformation. Additional features included optic atrophy, epilepsy, and abnormal EEG. One patient had hypopigmented nonitchy skin patches on the face and trunk.

Vodopiutz et al. (2015) reported 5 patients from 4 consanguineous families with GAMOS. One of the patients was a girl, born of consanguineous Turkish parents, previously reported by Steiss et al. (2005), who developed nephrotic syndrome at age 16 years. Common features of all patients included profound intellectual disability with poor or absent speech, axial hypotonia, microcephaly, feeding problems, and cerebellar atrophy. More variable features included short stature, seizures, ataxia, spasticity, dystonia, lack of mobility, optic atrophy, strabismus, retinopathy, and brain atrophy. One family had basal ganglia degeneration. Most patients had proteinuria; 2 died of renal failure at ages 2.5 and 17 years. However, Vodopiutz et al. (2015) emphasized the high inter- and intrafamilial variability concerning renal involvement with regard to age at onset and type of kidney disease, and noted that some patients may not even have renal disease.

Jinks et al. (2015) reported 30 Amish patients, ranging in age from 1 to 28 years, with GAMOS. The patients presented in infancy with roving nystagmus, visual impairment associated with progressive optic atrophy, irritability, and microcephaly with severely delayed psychomotor development. Only 10% achieved independent sitting or ambulation. Most developed extrapyramidal movements with axial dystonia and limb chorea. About 40% of children developed seizures, and EEG showed background slowing, multifocal sharp and spike-wave discharges, and rare hypsarrhythmia. Brain imaging showed diffuse cerebral atrophy, thin corpus callosum, and progressive cerebellar atrophy; gyral abnormalities were not observed. In addition, more than half (57%) of patients developed steroid-resistant proteinuria and progressive renal failure during early childhood. Death in 14 (47%) patients was due to complications of renal failure in most cases. Neuropathologic examination of 2 patients showed small brains with small sclerotic cerebella, small hindbrain, and thin corpus callosum. The cerebral cortex showed normal lamination. There was loss of striatal cholinergic interneurons, optic atrophy, and delamination of the lateral geniculate nuclei. The cerebella showed granule cell depletion, Bergmann gliosis, and signs of Purkinje cell deafferentation with asteroid bodies and dysmorphic dendritic trees. The findings were consistent with a profound disruption of cerebellar feedback to the nervous system, affecting visual, sensorimotor, and cognitive systems. Renal pathology showed focal segmental glomerulosclerosis (FSGS), thickened basement membrane, effacement of podocyte foot processes, fibrosis, and tubular atrophy.

Clinical Variability

Megarbane et al. (2001) reported a large inbred Lebanese family in which 5 children had severe developmental delay, psychomotor retardation, proportionate short stature, cerebellar spastic ataxia, microcephaly, optic atrophy, speech defect, abnormal osmiophilic pattern of skin vessels, and cerebellar atrophy. No evidence of metabolic disease was identified, and analysis of respiratory chain complex abnormalities was unremarkable. The authors suggested that these patients represent a novel autosomal recessive disorder. Delague et al. (2002) stated that the peculiar inversion of the usual osmiophilic pattern of the vessels observed in skin biopsies of children affected by this disorder, which they called CAMOS, had never been described in association with autosomal recessive nonprogressive congenital ataxia. Although the biologic and clinical significance of this observation was not evident, it was thought possible that the abnormal ultrastructure of the vessels prevented normal exchange between the blood and surrounding tissues, thus decreasing vessel permeability and modifying the production and/or migration of neuronal cells at an early stage. In a follow-up of the family reported by Megarbane et al. (2001), Vodopiutz et al. (2015) noted that none of the 5 patients had developed renal involvement by 25 to 31 years of age.

Inheritance

The transmission pattern of CAMOS in the families reported by Megarbane et al. (2001) and of GAMOS in the families reported by Colin et al. (2014) was consistent with autosomal recessive inheritance.

Mapping

Using identity by descent and DNA pooling (i.e., homozygosity mapping) in the Lebanese family reported by Megarbane et al. (2001), Delague et al. (2002) mapped the CAMOS disease locus to a 3.6-cM interval on chromosome 15q24-q26.

Molecular Genetics

In 3 patients from 2 unrelated families with GAMOS, Colin et al. (2014) identified 2 different homozygous truncating mutations in the WDR73 gene (616144.0001 and 616144.0002). The mutation in the first family was found by autozygosity mapping and exome sequencing; the second mutation was found in a patient ascertained from a cohort of 30 unrelated individuals with a similar phenotype who underwent direct sequencing of the WDR73 gene. Colin et al. (2014) presented evidence that WDR73 plays a role in regulation of the microtubule network during the cell cycle and suggested that loss of WDR73 function leads to impaired neuronal growth and brain development, as well as impaired podocyte growth and maintenance in the kidney.

In 2 sisters, born of consanguineous Arab parents, with GAMOS, Ben-Omran et al. (2015) identified a homozygous truncating mutation in the WDR73 gene (Q235X; 616144.0003). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Morpholino knockdown of the wdr73 gene in zebrafish resulted in brain growth and morphogenesis defects, and the Q235X mutation was unable to rescue the phenotype of wdr73-null zebrafish. The findings suggested that WDR73 has an important role in neural progenitor cell proliferation and differentiation, particularly during development.

In 10 individuals from 5 families with GAMOS, Vodopiutz et al. (2015) identified 5 different novel homozygous mutations, 2 truncating and 3 missense, in the WDR73 gene (616144.0004-616144.0008). The mutation in the first family was found by a combination of homozygosity mapping and whole-exome sequencing. Overall, WDR73 mutations were found in 3 (5.9%) of 51 patients with cerebellar atrophy and variable brain anomalies, and in 2 (5%) of 40 patients with a clinical diagnosis of GAMOS. The mutations, which segregated with the disorder in the families, were either not found or found at a very low frequency in the Exome Sequencing Project and ExAC databases. Functional studies of the variants were not performed. Some of the patients had late-onset or no renal involvement, thus expanding the phenotypic spectrum of the disorder. One of the families (family 2) reported by Vodopiutz et al. (2015) had previously been reported by Megarbane et al. (2001) and Delague et al. (2002). In this family, Nicolas et al. (2010) identified a homozygous variant in the ZNF592 gene (G1046R; 613624.0001) that was initially thought to be causative of the disorder. Vodopiutz et al. (2015) concluded that the WDR73 mutation identified in this family (H347Y; 616144.0005) was responsible for the phenotype, but a contribution from the ZNF592 variant could not be excluded.

In 27 Amish patients with GAMOS, Jinks et al. (2015) identified a homozygous truncating mutation in the WDR73 gene (616144.0009). The mutation, which was found by a combination of linkage analysis and exome sequencing, was confirmed by Sanger sequencing and segregated with the disorder in the families. Expression of WDR73 was weak and cytosolic in patient fibroblasts. Patient fibroblasts showed growth and proliferation defects with abnormal progression through the cell cycle and early senescence. None of the mutant cells were observed in any phase of the cell cycle outside of interphase, and this growth defect could be rescued by expression of wildtype WDR73. The truncated protein showed increased interaction with tubulins and heat-shock proteins compared to wildtype, suggesting that the overstabilization of these interactions may hinder normal WDR73 movement. The 3.9-Mb Amish autozygous block contained a second truncating variant in the WHAMM gene (612393), which may have contributed to the phenotype; additional studies of this variant were not performed.

Animal Model

Ben-Omran et al. (2015) found expression of wdr73 in the midbrain and hindbrain of zebrafish embryos. Morpholino knockdown of the wdr73 gene resulted in signs of developmental delay, such as curved and/or truncated tail, reduced head size, and brain morphology defects in the midbrain and cerebellum, including dilated ventricles and a reduction in progenitor cells. The remaining progenitor cells persisted abnormally in a proliferative state, suggesting a failure to exit the cell cycle, which was associated with a defect in neuronal differentiation. These neurodevelopmental defects could be rescued by wildtype wrd73. Mutant fish also showed hypopigmentation.