Galloway-Mowat Syndrome
A rare, genetic multisystem disorder characterized by a neurodegenerative disorder associating global developmental delay, progressive microcephaly, and progressive cerebral and cerebellar atrophy with extrapyramidal involvement, progressive optic atrophy, and in many patients early-onset steroid-resistant nephrotic syndrome.
Epidemiology
More than 100 cases have been reported to date. Males and females are equally affected.
Clinical description
Disease onset is typically within the first few months of life, but may be detected in childhood with later onset nephrotic syndrome (NS). Clinical manifestations, primarily involving the kidney and central nervous system, are heterogeneous. Renal manifestations range from isolated proteinuria to full blown early-onset nephrotic syndrome (NS), which is multidrug resistant and rapidly progresses to end-stage kidney disease (ESKD). Neurodegenerative manifestations include progressive microcephaly of prenatal or postnatal onset, global development delay and often severe intellectual disability (most patients never reach independent ambulation and are not verbal) and, more variably, epilepsy, hypotonia, ataxia, spasticity and extrapyramidal dystonia. Structural brain abnormalities are variable and include neural migration defects (lissencephaly-pachygyria spectrum), cerebellar and cortical atrophy, ventricular dilation, encephalomalacia, porencephaly, leukomalacia, generalized hypomyelination, and/or thin corpus callosum. Dysmorphic features include short stature, facial dysmorphism (including a high, narrow forehead, hypertelorism, almond-shape eyes, large and low set ears, and micrognathia) and more variably arachnodactyly, camptodactyly and clasp thumb. Additional frequent features include hiatus hernia and ocular abnormalities (progressive optic atrophy, nystagmus and strabismus).
Etiology
Galloway-Mowat is a genetically heterogeneous condition with causative mutations in at least seven genes, four of which code subunits of Kinase, Endopeptidase and Other Proteins of small Size (KEOPS) complex. The most common form is associated with variations in OSGEP (14q11), are associated with early onset NS (median age 3 months). Whereas, mutations in WDR73 (15q25.2), encoding WD repeat-containing protein 73, or NUP107 (12q15), encoding Nuclear pore complex protein Nup107, are typically associated with a later onset NS.
Diagnostic methods
The coexistence of albuminuria and CNS abnormalities, or of CNS anomalies and functional visual impairment in infants and children is suggestive of the diagnosis. Molecular analysis may confirm the diagnosis.
Differential diagnosis
The main differential diagnoses include Pierson syndrome, ARHGDIA mutations, coenzyme Q deficiency, other mitochondrial disorders, sialidosis and congenital disorders of glycosylation. In patients with no renal involvement at the time of assessment, differential diagnosis extend to syndromes with progressive microcephaly (including those of prenatal onset) and CNS malformations such as the complex cortical dysplasias with other brain malformations (which encompass among others several dominant syndromes causes by mutation in the tubulin genes).
Antenatal diagnosis
The occurrence of microcephaly and intra-uterine growth retardation with oligohydramnios in late second trimester suggests the diagnosis and fetal MRI is recommended as further investigation. In cases with an identified causative mutation, prenatal diagnosis can be offered to the family.
Genetic counseling
The pattern of inheritance is either X-linked (LAGE3) with a 50% risk of recurrence in male siblings of a carrier mother, or autosomal recessive with a 25% risk of recurrence in both male and female siblings.
Management and treatment
There is no specific treatment available. Epilepsy may be intractable. The nephrotic syndrome does not respond to either steroid or immunosuppressive therapy. Renal transplant may be considered for ESKD. Multidisciplinary approach is encouraged to offer a global symptomatic care.
Prognosis
The prognosis is poor; children with early-onset NS typically die during the first year of life due to ESKD. Longer survival is reported for children with later onset NS.