OMIM ID:
Sengers Syndrome
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
This is a mitochondrial DNA depletion syndrome in which congenital cataracts are the hallmark ocular feature. The bilateral lens opacification is usually total at birth or within the first few weeks of life as manifested by leucocoria. Lens extraction is necessary within the first 6 months of life but visual rehabilitation is nearly always compromised postoperatively by nystagmus and strabismus. In one series only one eye recovered to 20/40 but the average postoperative acuity was in the range of 20/200 and virtually all students require special education in schools for the visually impaired. Axial myopia is common with most patients having myopic fundus changes and requiring less than +10 diopters of aphakic correction. Pale optic disks and a pigmentary retinopathy were noted among 8 of 18 eyes in one series. Mild and inconsistent dyschromatopsia has been reported in a few patients. The ERG sometimes shows diminished rod and cone function.
Systemic Features
Hypertrophic cardiomyopathy is often diagnosed within a fews days after birth but 40% may escape detection until the second or third decade of life. It is usually progressive and often fatal in the neonatal period. Myopathy involves both cardiac and skeletal muscles. Generalized hypotonia, exercise intolerance, and delayed motor development are important features in the majority of patients. Metabolic lactic acidosis occurs with relatively minimal excercise. Skeletal muscle biopsies show ragged-red fibers with combined deficiencies of mitochondrial complexes I, III, and IV along with severe depletion of mtDNA. Increased urine levels of 3-methylglutaconic have been reported.
The central nervous system is usually not involved and mental development is normal if lactic acidosis is controlled. However, several children with mental retardation have been reported.
Genetics
Inheritance
Homozygous or compound heterozygous mutations in AGK (7p34), a lipid metabolism gene, are responsible for this condition. There is considerable variation in the severeity of the phenotypic features but no ocular or cardiac disease has been found in heterozygotes.
The same gene was found to be mutated in an autosomal recessive congenital cataract (614691) in a single reported sibship. Thorough systemic evaluation found no evidence of cardiac and skeletal muscle disease.
Pedigree
Autosomal recessive
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.
In order for autosomal recessive disorders to be expressed, offspring generally must inherit two mutations, one from each carrier parent. Carriers with only one mutation, such as the parents, do not have clinical disease. Note that carrier parents can expect that 1 in 4 children (25%) will inherit both mutations and have the disorder, 2 in 4 children (50%) will be carriers like their parents, while 1 in 4 children (25%) inherit neither mutation.