MELAS (mitochondrial encephalomyopathy with lactic acidosis and strokelike episodes) is an example of a mitochondrial disorder. Normal in early childhood, individuals affected with MELAS develop episodic vomiting, seizures, and recurrent cerebral insults that resemble strokes between 5 and 10 years of age. In 80% of cases, analysis of the mtDNA reveals a specific mutation (A3242G) in MTTL1, a gene that codes for a mitochondrial transfer RNA.
In families in which MELAS occurs, a range of symptoms is seen in first-degree relatives, including progressive external ophthalmoplegia, hearing loss, cardiomyopathy, and diabetes mellitus. Although all offspring of a woman who carries a mutation would be affected, because of heteroplasmy, the severity of disease varies, depending on the percentage of mitochondria bearing the mutation that are present.
Evaluation of a child with uniparental disomy (UPD) reveals a normal karyotype. However, chromosomal markers for one particular chromosome are identical to the markers found on the chromosomes of the patient’s mother or father (but not both). In UPD, the individual inherits two copies of one parent’s chromosome and no copy from the other parent.
UPD probably occurs through a few mechanisms, but the most common results from a spontaneous rescue mechanism. At the time of conception, through nondisjunction, the fertilized egg is trisomic for a particular chromosome, with two copies of one parent’s chromosome and one copy of the other parent’s chromosome; conceptuses with trisomy often miscarry early in development. Fetuses with UPD survive because they spontaneously lose one of three copies of the affected chromosome. If the single chromosome from one parent is lost, the patient has UPD.
An alternate explanation involves monosomy for a chromosome rather than trisomy. Had the conceptus, at the time of conception, inherited only a single copy of a chromosome, spontaneous duplication of the single chromosome would lead to UPD.
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Prader-Willi syndrome (PWS), which occurs in approximately 1 in 10,000 infants, is characterized by hypotonia of prenatal onset; postnatal growth delay; a characteristic appearance, including almond-shaped eyes and small hands and feet; developmental disability; hypogonadotropic hypogonadism; and obesity after infancy. Early in life, affected infants are so hypotonic that they cannot consume enough calories to maintain their weight. Nasogastric feeding is invariably necessary, and failure to thrive is common. During the first year of life, muscle tone improves and children develop a voracious appetite. Some 60% to 70% of individuals with PWS have a small deletion of chromosome 15 (15q11). In individuals without a deletion, 20% have UPD of chromosome 15.
Angelman syndrome (AS) is a condition with moderate to severe mental retardation, absence of speech, ataxic movementsof the arms and legs, a characteristic craniofacial appearance,and a seizure disorder that is characterized by inappropriatelaughter. AS is also characterized by a deletion in the 15q11region in 70% of affected individuals; UPD for chromosome15 can be demonstrated in approximately 10% of AS patients.
If the deletion occurs in paternal chromosome 15, the affected individual has PWS, whereas AS results from a deletion occurring only in the maternal chromosome 15. When UPD is responsible, maternal UPD results in PWS, whereas paternal UPD results in AS. To summarize, if a copy of paternal chromosome 15q11.2 is lacking, PWS occurs; if maternal chromosome 15q11.2 is lacking, AS results.