Mitochondrial Diseases

Kearns-Sayre syndrome (KSS) (OMIM phenotype number #530000)
Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) (OMIM phenotype number #540000)
Mitochondrial trifunctional protein deficiency (MTPD) (OMIM phenotype number #609015)
Medium chain acylCoA dehydrogenase deficiency (ACADMD) (OMIM phenotype number #201450)

Mitochondrial diseases are a group of diseases caused by impairment of the respiratory chain. The prevalence is approximately 1–2/10.000. These disorders are subdivided in two groups: the disorders due to defects in mtDNA (mitochondrial DNA) and due to defects in nuclear DNA. MtDNA-related diseases are inherited according to the rules of mitochondrial genetics (maternal inheritance, heteroplasmy and the threshold effect, mitotic segregation), and mitochondrial diseases caused by abnormalities in nuclear DNA are inherited according to the Mendelian rules. The clinical features may be multisystem, involving visual and auditory pathways, heart, central nervous system, and skeletal muscle. The “red flags” are myopathy characterized by exercise intolerance, eyelid ptosis, ophthalmoparesis, axonal multifocal neuropathy, sensorineural hearing loss, pigmentary retinopathy, optic neuropathy, diabetes mellitus, hypertrophic cardiomyopathy, migraine-like headache, and short stature. Hypoparathyroidism is a very rare clinical manifestation among these diseases. Diagnosis of mitochondrial disease is based on biochemical exams, such as measurements of serum lactate at rest and after exercise, electromyography, muscle histology and enzymology, and molecular analysis. Serum creatine kinase concentrations are normal or moderately elevated. A specific and reliable biomarker is not available yet. In the most of cases, muscle biopsy is still necessary if there is a suspected mitochondrial disease. Mitochondrial hypoparathyroidism typically has a pediatric onset.

Kearns-Sayre syndrome (KSS) is a multisystemic disease defined by the following obligatory triad:
onset before age 20 years, pigmentary retinopathy, progressive external ophthalmoplegia. At least one of the following must also be present: cardiac conduction block, cerebrospinal fluid protein concentration greater than 100 mg/dL, and cerebellar ataxia. Other possible clinical features include short stature, hearing loss, dementia, limb weakness, diabetes mellitus, hypoparathyroidism, and growth hormone deficiency. Treatment of KSS is supportive.

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a rare progressive multisystemic disease. First onset of symptoms is frequently between ages two and ten years (in some cases delayed onset between ages 10 and 40 years). The clinical diagnosis of MELAS is based on the following features: stroke-like episodes, typically before age 40 years, encephalopathy with seizures and/or dementia, and mitochondrial myopathy, evidenced by lactic acidosis and/or ragged red fibers on muscle biopsy. Two of the following are also required to confirm the diagnosis: normal early psychomotor development, recurrent headache, and recurrent vomiting. No specific treatment for MELAS exists.

Mitochondrial trifunctional protein deficiency (MTPD) is a very rare autosomal recessive disease of fatty acid oxidation characterized. This disorder is characterized by a wide heterogeneous clinical presentation with severe neonatal manifestations including cardiomyopathy, hypoglycemia, metabolic acidosis, skeletal myopathy and neuropathy, liver disease and death to a mild phenotype with peripheral polyneuropathy, episodic rhabdomyolysis and pigmentary retinopathy. There are two forms of MTPD, severe form (neonatal onset), and a moderately severe form (onset usually from the neonatal period to 18 months of age). Both forms can manifest with neuropathy with or without cardiomyopathy and can be fatal. Treatment management consists of a low fat diet with restriction of long chain fatty acid intake and substitution with medium chain fatty acids.

Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) is an autosomal recessive disorder of mitochondrial fatty acid oxidation, often diagnosed in infancy or through neonatal screening. MCADD may be suspected in a previously healthy individual who becomes symptomatic with hypoketotic hypoglycemia, lethargy, seizures, coma triggered by a common illness, epatomegaly and acute liver disease. The first acute episode usually occurs before age two years, but affected individuals may present at any age including adulthood. The treatment in symptomatic patients is based on simple carbohydrates by mouth (e.g., glucose tablets, or sweetened, non-diet beverages) or IV if needed to reverse catabolism and sustain anabolism. The prevention of clinical manifestations is based on avoidance of fasting and weight control measures including proper nutrition and exercise.


KSS: gene, mitoc. DNA.
MELAS: gene, mitoc. DNA.
MTPD: HADHA gene, 2p23.3 (OMIM gene/locus number #600890); HADHB gene, 2p23.3 (OMIM gene/locus number #143450).
ACADMD: ACADM gene, 1p31.1 (OMIM gene/locus number #607008).


Severe multiorgan conditions, with high perinatal lethality, sometimes associated with hypoparathyroidism.

Main biochemical alterations

Low Ca, high Pi, low/undetectable PTH, low 1,25(OH)2D, high CSF proteins (>100 mg/dl), low CSF folic acid, lactic acidosis, low serum and muscle coenzyme Q. ACADMD: also low plasma carnitine levels.


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