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Neurodevelopmental Disorder with Progressive Microcephaly, Spasticity, and Brain Anomalies

Neurodevelopmental Disorder with Progressive Microcephaly, Spasticity, and Brain Anomalies

Patient Information

Characteristics

Background and History

This is a rare inherited disorder of brain development with severe, progressive neurological deficiencies.

Clinical Correlations

Infants appear ‘floppy’ at birth and spontaneous movements are limited.  This results in poor feeding activity and difficulty breathing.  There is little developmental progression.  Severe cognitive delays result in profound mental retardation in most cases.  Seizures are common.

Physical signs include low-set and posteriorly rotated ears, a short nose, a highly arched palate, a short lower jaw, excess hair, stiff large joints and highly flexible small joints, a deformity of the breastbone, and sometimes extra digits.  The skull appears abnormally small and falls behind as the body grows.

MRI brain imaging reveals a large variety of deficits some which are progressive.  These can result in an early demise, in infancy or early childhood, usually from respiratory difficulties. 

Genetics

Inheritance

This is an autosomal recessive disorder resulting from mutations in both members of a specific pair of genes.  Parents who carry one copy are clinically normal but when both carry a single copy of the mutation they confer a 25% risk of this condition to each of their offspring.

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.

Sample pedigree of autosomal recessive inheritance

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.

Diagnosis and Prognosis

The clinical features described here could lead to the suspected diagnosis at birth or during the neonatal period.  Special attention should be directed to maintaining respiratory function.  This likely requires teamwork among ophthalmologists, pediatricians, neurologists, and orthopedists.  Brain imagining and gene studies are necessary to confirm the diagnosis.

No treatment has been reported and the prognosis is poor.

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