developmental delay

Infants are usually born with a normal head circumference but fall behind (2 SD or more) in the first year.  They have neonatal and infantile central hypotonia with brisk peripheral tendon reflexes during early childhood.  They are sometimes described as drowsy or lethargic.  Facial and limb edema can be extensive but transient sometimes and can disappear later in childhood.  The fingers are tapered.  The cheeks are full, the mouth is usually open and the upper lip appears 'tented'.  Global developmental delay is common and normal milestones are seldom attained.  Some patients have been described as severely retarded mentally.  Infantile spasms and myoclonic jerkingcan be seen within the first months of life while frank seizures with hypsarrhythmia are common in the first year of life.  Status epilepticus is a common occurrence.  General drowsiness and poor feeding are often features.  Death usually occurs in infancy or early childhood.  Midface hypoplasia and micrognathia are often present.

Brain imaging (MRI) and histology show severe alterations in myelination and cellular organization.  Neuronal loss is seen in the inner granular layer of the cerebellum but there is relative preservation of Purkinje cells.  General and progressive atrophy of the cerebellum and brain stem have been described.

Among the three reported individuals with the COL4A3BP mutation, one had postnatal microcephaly, widely spaced teeth, synophrys, and intellectual disability. Another had trunk hypotonia, global developmental delay, wide intermamillary distance, 2-3 toe syndactyly, tonic-clonic seizures, and myopathic facies. The third had a broad-based gait, coarse and curly hair, tonic-clonic seizures, and global developmental delay. 

Infants are born with low birth weight due to intrauterine growth retardation and there is often a history of oligohydramnios.  Newborns are often floppy and hypotonic although spasticity may develop later.  A small midface and microcephaly (80%) with a sloping forehead and a flat occiput are frequently evident.  The ears are large, floppy, and low-set while the hard palate is highly arched and the degree of micrognathia can be severe.  The fists are often clenched and the digits can appear narrow and arachnodactylous.  Hiatal hernias may be present.

Many patients develop features of the nephrotic syndrome in the first year of life with proteinuria and hypoalbuminemia due to glomerular kidney disease and renal system malformations.  Renal biopsies show focal segmental glomerulosclerosis in the majority of glomeruli.

Evidence of abnormal neuronal migration with brain deformities such as cystic changes, porencephaly, encephalomalacia, and spinal canal anomalies have been reported.  MRI imaging shows diffuse cortical and cerebellar atrophy atrophic optic nerves, and thinning of the corpus callosum.  The normal striated layers of the lateral geniculate nuclei are obliterated.  The cerebellum shows severe cellular disorganization with profound depletion of granule cells and excessive Bergmann gliosis.  The vermis is shortened. 

Multifocal seizures are sometimes (40%) seen in infancy and early childhood and the EEG generally shows slowed and disorganized backgound and sometimes a high-voltage hypsarrhythmia.  The degree of psychomotor delay and intellectual disability is often severe.   Most patients are unable to sit independently (90%), ambulate (90%), or make purposeful hand movements (77%).  The majority (87%) of children have extrapyramidal movements and a combination of axial dystonia and limb chorea.  Mean age of death is about 11 years (2.7 to 28 years in one series) and most die from renal failure.