OMIM ID:
Neurodevelopmental Disorder, Mitochondrial, with Abnormal Movements and Lactic Acidosis
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
Optic atrophy is sometimes present. Nystagmus, and strabismus are seen in some patients. A pigmentary retinopathy was found in one individual.
Systemic Features
This is a clinically heterogeneous disorder with extensive neurological deficits. Patients have feeding and swallowing difficulties from the neonatal period. There is intrauterine growth retardation and postnatally patients usually exhibit psychomotor delays and intellectual disabilities. Some develop seizures and few achieve normal developmental milestones. Axial hypotonia is present from early infancy and most patients have muscle weakness and atrophy. However, there may be spastic quadriplegia which is often associated with dysmetria, tremor, and athetosis. Ataxia eventually develops in most patients.
Brain imaging shows cerebral and cerebellar atrophy, enlarged ventricles, white matter defects, and delayed myelination.
Incomplete metabolic studies suggest there may be abnormalities in mitochondrial oxidative phosphorylation activity in at least some tissues. Most patients have an elevated serum lactate.
Death in childhood is common.
Genetics
Inheritance
Homozygous and compound heterozygous mutations in the WARS2 gene have been found in several families with this condition. The considerable variation in the phenotype may at least partially be explained by the fact that an additional variant in the W13G gene is sometimes present which impairs normal localization of the WARS2 gene product within mitochondria.
The transmission pattern in several families is consistent with autosomal recessive inheritance.
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.