OMIM ID:
Mitochondrial DNA Depletion Syndrome 1
Alternate Names
Defective Genes
Clinical Characteristics
Ocular Features
Progressive external ophthalmoplegia has an adult onset, usually in the late second or early third decade of life. Ptosis is commonly present as well.
Systemic Features
This condition has been called a mitochondrial neurogastrointestinal encephalopathy (MNGIE). Gastrointestinal problems are among the most disabling with poor absorption of foodstuffs leading to weight loss, marked cachexia, and chronic malnutrition. Added to this are gastroparesis, constipation, vomiting, and intermittent diarrhea with abdominal pain. Many individuals develop diverticulosis and diverticulitis that may lead to intestinal perforations. The combined intestinal dysfunctions can lead to signs of intestinal pseudoobstruction.
Many patients have a progressive sensorineural hearing loss. Leukoencephalopathy, sensorimotor peripheral neuropathy, and sometimes mild proximal limb weakness may be present.
Genetics
Inheritance
Homozygous and compound heterozygous mutations in the TYMP gene (22q13.33) are responsible for this autosomal recessive disorder. This nuclear gene is active in the maintainence of mitochondrial DNA. When the gene is dysfunctional, the mitochondria can be depleted to a variable extent and they may contain multiple deletions and point mutations.
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.