Clinical Characteristics
Ocular Features
Severe visual impairment is noted before one year of age when infants cease following objects in their environment. Cortical visual impairment has been diagnosed although ‘atrophic optic fundi’ and hypotrophic optic nerves and fovea have also been described. Nystagmus has been observed as well.
Systemic Features
Microcephaly relative to age norms is evident usually by 2 months of age and there is little subsequent growth of the skull. Regression of developmental milestones is noted by 4 months of age with signs of irritability, akathisia, spasticity, visual impairment, seizures, and increased startle responses. Sucking responses and eye-to-eye contact are usually lost by 6 months of age. Repetitive body stiffening and extension of arms in older individuals consistent with seizure activity has been confirmed by EEG in at least one infant. Imaging consistently reveals cerebral atrophy with ventriculomegaly and general loss of brain volume. Progressive muscle weakness is evident after about 1 year of age and oral feeding is impaired. There is complete lack of responsive interaction beyond irritability and agitation while motor function is limited to involuntary responses. Two individuals have lived into the second decade of life.
Genetics
Inheritance
This condition has been described in 4 individuals who were products of consanquineous Amish couples. Homozygous mutations in the TMPRSS4 gene (11q23.3), whose product is a serine transmembrane protease, seems to be responsible.
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.