Background
Galloway–Mowat syndrome (GAMOS) is a rare autosomal recessive disorder characterized by early-onset steroid-resistant nephrotic syndrome (SRNS) and microcephaly with brain anomalies [
1]. It was originally described in 1968 in two siblings with the triad of congenital nephrotic syndrome, microcephaly, and hiatus hernia [
1]. Since then, more than 60 patients have been reported in the literature and heterogeneous clinical and histopathological phenotypes were reported. Renal presentations range from asymptomatic proteinuria to SRNS. Although early-onset nephrotic syndrome is more common, later onset during childhood has also been reported. Diverse central nervous system anomalies and the involvement of multiple organs were also reported. However, the appearance of a hiatal hernia was found to be inconsistent and is no longer considered essential for the diagnosis. At present, its clinical spectrum has also expanded to include craniofacial dysmorphism, abnormality of extremities, seizure disorder, developmental delay, psychomotor retardation, hypotonia, and a variety of neuropathological findings as well as heterogeneous renal histopathology. Although some authors have tried to classify GAMOS according to the clinical presentation [
2,
3], no classification is currently accepted. Recent studies have unmasked important genetic mutations in some patients with GAMOS. Homozygous mutations in
WDR73 (OMIM *251300) were first implicated in patients with GAMOS reported by Colin et al. in 2014 and later studies [
4‐
8]. Very recently, via whole exon sequencing and high throughput exon sequencing, Braun and colleagues identified mutations in Kinase, Endopeptidase and Other Proteins of small Size (KEOPS) complex genes responsible for GAMOS (OMIM *301006, *617729, *617730, *617731) [
9].
The KEOPS complex is required for a universal tRNA modification, known as the N
6-threonyl-carbamoyl-adenosine (t
6A) modification, which is necessary for translational accuracy and efficiency [
10]. The complex is composed of 4 subunits:
LAGE3,
OSGEP,
TP53RK, and
TPRKB. A fifth member of the complex,
C14ORF142, has been identified recently [
11]. Braun et al. screened the coding regions of
LAGE3,
OSGEP,
TP53RK, and
TPRKB in 907 patients with nephrotic syndrome, including 91 individuals with GAMOS, all of which were collected through an international collaborative effort. They narrowed the group down to 37 patients with GAMOS from 32 different families with mutation in these 4 genes. Specifically, recessive
OSGEP mutations were identified in 28 patients from 24 families, including our 5 patients with mutations of
OSGEP gene on chromosome 14q11 [
9]. The term “Galloway-Mowat syndrome 1 (GAMOS1)” is now used for GAMOS caused by mutations in
WDR73, and “Galloway-Mowat syndrome 2-5 (GAMOS2-5)” is used for GAMOS with mutations in
LAGE3,
OSGEP,
TP53RK, and
TPRKB, respectively [
9]. The purpose of this study was to present our experience in the diagnosis of GAMOS3 in Taiwan with a particular emphasis on the characteristic clinical and imaging findings.
Discussion
Since 1968, more than 60 cases of GAMOS have been reported with an expanding spectrum of phenotypic findings. Nephrotic syndrome with microcephaly has histologically been the major diagnostic criteria of GAMOS. These reported cases labeling GAMOS had renal involvement ranging from isolated proteinuria to early- or late-onset nephrosis, and large varieties of brain abnormalities such as primary or secondary (postnatal) microcephaly, cerebral or cerebellar atrophy, and neural migration defects [
8]. Given its clinical heterogeneity, GAMOS is believed to be a genetically heterogeneous group of disorders. In this study, we report on a group of 6 patients with an identical
OSGEP gene mutation (c.740G > A transition) who exhibited a uniform clinical phenotype with early-onset SRNS, craniofacial and skeletal dysmorphism, primary microcephaly with cerebral pachygyria, and early death before 2 years of age. In the study by Braun et al., with only one exception, 9 out of 10 GAMOS patients of Taiwanese ethnic origin were found to have a c.740G > A transition in the
OSGEP gene [
9]. On the basis of a shared the same
OSGEP gene mutation and geographical location, preliminary evidence suggested the presence of a founder effect among GAMOS cases in the Taiwan population. The frequency of reports of GAMOS from Taiwan is striking considering the extreme rareness of this syndrome [
14‐
17]. This is very likely due to a high allele frequency of the founder mutation that has been demonstrated in almost all Taiwanese cases. The Exome Aggregation Consortium (ExAC;
http://exac.broadinstitute.org) gives an allele frequency for this mutation of 0.0008 in the East Asian population [
18]. This would anticipate an incidence of the disease of about 1 in a million in this population. The frequency in subpopulations of East Asia may be even higher.
Our cases are consistent with the group of patients with true GAMOS (microcephaly, gyral abnormalities, and early-onset nephrotic syndrome) proposed by Meyers and Keith [
3,
19]. Meyers et al. suggested that the term GAMOS should be reserved for patients with early-onset nephrotic syndrome, microcephaly with gyral abnormalities, and death in early childhood [
3]. From a pathological point of view, Keith et al. showed that children with disordered neuronal migration tend to have a worse prognosis (true GAMOS), and those without gyral abnormalities have a better prognosis [
19].
Although previous studies had documented the facial dysmorphic features as minor and not specific to this syndrome [
3,
14], all of our patients were born with an aged face with the features such as large and floppy ears, micrognathia, hypertelorism, microphthalmia, sunken eyeballs, coarse hair, a narrow or receding forehead, a beak nose, and prominent glabella with a broad nasal bridge. These dysmorphic facies can be an important factor in the diagnosis of GAMOS. For our patients II and III-1, with these typical characteristic facies after birth, GAMOS was highly suspected and signaled the need to verify the existence of proteinuria. Edema and nephrotic syndrome then developed later during a subsequent follow-up. Arachnodactyly or camptodactyly was noted in all of our patients (caused by an
OSGEP mutation) and has been frequently observed in Taiwanese patients affected with GAMOS [
9,
14‐
17]. This geographic difference may be due to our special founder mutation in the
OSGEP gene (c.740G > A transition) specific to Taiwanese patients. It is also possible that it was present in the other reported GAMOS patients but not included in the published papers either because it went unnoticed or was not considered a distinctive enough feature worth mentioning.
Typical brain MRI findings for true GAMOS include a spectrum of gyration abnormalities ranging from lissencephaly to pachygyria and polymicrogyria, myelination defect, and cerebellar hypoplasia. The clinical neurologic manifestations in our patients included microcephaly at birth (6/6), global developmental delay (6/6), hypotonia (6/6), intractable seizure (5/6), and structural brain abnormalities, including pachygyria (6/6), myelination defect (4/6), and cerebellar hypoplasia (1/6). In our country, all pregnant women are permitted a routine prenatal ultrasound that is covered by the National Health Insurance. Although the kidneys are unremarkable at the fetal stage, the prenatal significant sonographic triad includes microcephaly (6/6), intrauterine growth retardation (6/6), and oligohydramnios in the second or third trimester (5/6). It implies that the neurological and growth abnormalities are universal in children with GAMOS3, often precede renal symptoms [
20], and even begin during the prenatal stage. Fetal ultrafast MRI can be used for prenatal diagnosis and assessment of fetal sulci, gyral abnormalities, and cerebellar atrophy, as in 2 of our patients. An in vivo, knockout of orthologous KEOPS subunit genes in zebrafish and mouse recapitulated the primary microcephaly phenotype but not the renal phenotype seen in GAMOS patients [
9]. The early lethality in animal models could have masked the renal presentation that might have been seen in older animals.
Concerning the renal involvement, all our patients developed early-onset (6 days-7 weeks) nephrotic syndrome. Previously reported glomerular findings on a light microscope were inconsistent and may have varied from minimal change disease, focal segmental glomerulosclerosis, diffuse mesangial sclerosis, collapsing glomerulopathy, or microcystic dysplasia [
14,
20] and were also described in patients with GAMOS3 [
9]. The inconsistencies may be due to evaluation of patients at different ages or stages of the disorder [
14]. Using an electron microscope, our previous study suggested the pathognomonic pathological features of “true GAMOS” were irregular thickness of the glomerular basement membranes and the effacement of foot processes [
14]. An in vivo study recently showed that knockdown of
OSGEP and
TP53RK resulted in defects in the actin cytoskeleton and a decrease of human podocyte migration rate [
9]; these findings are compatible with the pathological manifestation in the development of nephrotic syndrome [
9]. The prognosis for patients with GAMOS3 is poor. All of our patients had SRNS, followed shortly by end-stage renal disease and early death.
The N
6-threonyl-carbamoyl-adenosine (t
6A) modification, one of the numerous post-transcriptional tRNA modifications, is a complex modification of adenosine located at position 37 (t
6A37) next to the anticodon stem loop of many tRNAs that decode ANN codons. The absence of this modification is associated with a severe growth phenotype in yeast [
21]. Edvardson et al. postulated that
OSGEP mutation exerts its pathogenic effect by perturbing t
6A synthesis, thereby interfering with global protein production, which leads to neurodegeneration and renal tubulopathy [
22]. By knockdown of
OSGEP using shRNA in human podocytes in vitro, Braun et al. further proved that
OSGEP mutations impair the functions of the KEOPS complex, resulting in disturbed translation, endoplasmic reticulum stress, dysfunctional DNA damage response, disturbance of actin regulation, and ultimately apoptosis [
9].
The features of our patients are different from patients with
WDR73-positive GAMOS (GAMOS1). Table
2 lists the different presentations of patients with GAMOS3 and GAMOS1.
WDR73 plays an important role in the maintenance of cell architecture and cell survival [
4]. Patients with
WDR73-positive GAMOS are rarely associated with the typical GAMOS phenotype, but rather present with a predominantly infantile-onset neurodegenerative disease with variable renal involvement [
7]. Mutations of
WDR73 are only found in a small subset (2/31 and 2/40) of patients with GMOS [
4,
7]. The main clinical manifestations included postnatal microcephaly, a coarse face, severe intellectual disability, seizures, cerebellar ataxia, optic atrophy, and late-onset nephrotic syndrome [
4‐
8]. Kidney involvement typically occurs in later years (2–8 years of age, median age, 5) with mostly slow progressing nephrotic syndrome [
4‐
8]. The most consistent finding on brain MRI is cerebellar atrophy. Cerebellar atrophy is present for all GAMOS1 patients reported so far and is considered a notable predictive feature for diagnosis of the
WDR73 mutation [
4‐
7]. Cerebellar atrophy was also found in 9 out of 28 patients with
OSGEP mutations [
9], including our patient III-2. However, gyral abnormalities and myelin defect were not present in patients with
WDR73-positive GAMOS. These differences are important for diagnostic, therapeutic, prognostic, and genetic counseling purposes.
Table 2
Different presentations between patients with GAMOS3 and GAMOS1
Mutant gene | OSGEP on chromosome 14q11 | WDR73 on chromosome 15q25 |
Pattern of inheritance | Autosomal recessive | Autosomal recessive |
Frequency in patients with GAMOS | High (24 of 32 families) [ 9] | Low (2 of 31 or 2 of 40 families) [ 4, 7] |
Facial dysmorphism | The aged face comprising features: Narrow forehead, large floppy ears, deep-set eyes, coarse hair, beaked nose, prominent nasal bridge, microphthalmia, hypertelorism, micrognathia, high-arch palate [ 9, 14‐ 17] | Coarse facial features: full lips and cheeks, broad forehead, bushy eyebrows, flat nasal root with fleshy nasal tip [ 8] |
Skeletal deformity | Arachnodactyly, camptodactyly, clenched hands | No |
Renal features |
Age of onset of proteinuria | Early-onset (< 3 months) | Late-onset |
Degree of renal disease | Heavy proteinuria with Nephrotic syndrome | Variability, from no renal involvement, mild proteinuria, to nephrotic syndrome |
Renal lesions | Light microscope: minimal change disease, focal segmental glomerulosclerosis (FSGS), diffuse mesangial sclerosis, collapsing glomerulopathy, or microcystic dysplasia [ 9] | Light microscope: FSGS, collapsing FSGS [ 4, 8] |
| Electron microscope: foot process effacement, irregular thickness of the glomerular basement membranes [ 9, 14] | Electron microscope: podocyte hypertrophy [ 4, 8] |
End stage renal disease | Common | Rare |
Neurological features |
Microcephaly | Primary (prenatal) microcephaly | Secondary (postnatal) microcephaly |
Clinical presentations | Severe psychomotor retardation, global developmental delay, hypotonia, intractable seizure | Neurodegenerative course, developmental delay, seizure, intellectual disability, cerebellar ataxia, optic atrophy [ 4‐ 8] |
Brain MRI | Gyral abnormalities (all): lissencephaly, pachygyria, or polymicrogyria Myelination defect (most) Cerebellar atrophy (some, 9 of 28) [ 9] | Cerebellar atrophy (all) [ 4‐ 8] Other abnormalities: thin corpus callosum, brain stem hypoplasia [ 4‐ 8] |
Prenatal ultrasonographic findings | Microcephaly, intrauterine growth retardation, and oligohydramnios | No specific findings |