Mitochondrial DNA depletion syndrome
Mitochondrial DNA depletion syndrome (MDS) is a rare autosomal recessive disorder characterized by a significant reduction in mitochondrial DNA (mtDNA) copy number in affected tissues without mutations in the mtDNA itself. It primarily affects infants and children and can manifest in several forms, including myopathic, encephalomyopathic, and hepatocerebral variants, each with distinct clinical features and age of onset. Symptoms can range from severe hepatic failure and muscle weakness to neurological impairments such as seizures and developmental delays. The condition stems from mutations in specific nuclear genes that are crucial for mtDNA maintenance and metabolism, leading to biochemical imbalances. Diagnosis is typically confirmed through genetic testing and biochemical assays. While treatment focuses on symptom management, including possible liver transplantation in severe cases, there is currently no curative therapy available. Genetic counseling and prenatal testing can offer support for affected families, particularly when known mutations are involved. Understanding the genetic and clinical complexities of MDS is essential for effective management and support of individuals and families impacted by this condition.
Mitochondrial DNA depletion syndrome
ALSO KNOWN AS: MDS; mitochondrial DNA depletion myopathy; Navaho neurohepatopathy; Alpers-Huttenlocher hepatopathic poliodystrophy; sensory ataxic neuropathy with dysarthria and ophthalmoplegia (SANDO); and spinocerebellar ataxia-epilepsy syndrome (SCAE)
DEFINITION Mitochondrial DNA depletion syndrome (MDS) is an autosomal recessive disease caused by defects in the nuclear-mitochondrial intergenomic communication and is characterized by a reduction in mitochondrial DNA (mtDNA) copy number in affected tissues, with no mutations in the mtDNA.
Risk Factors
MDS is a relatively common mitochondrial disease affecting infants and children. Age at onset varies in the different forms of the disease. In the hepatocerebral form, the onset is from birth to six months, and death occurs in the first year due to hepatic failure. In the myopathic form, onset is from birth to two years, and death typically occurs in infancy or childhood due to respiratory failure. A benign late-onset form occurs between one week and five years of age, and death typically occurs before age fifteen due to respiratory failure. MDS is inherited as an autosomal recessive trait, and mutations in eight nuclear genes are known to cause MDS. Depletion can also be caused by antiretroviral analogs that are used to treat patients with HIV. In this case, the depletion is reversible upon withdrawal of the drugs.
Etiology and Genetics
MDS is an autosomal recessive disease resulting in low copy number (amount) of mitochondrial DNA (mtDNA). Parents of patients are asymptomatic. Maintenance of the mitochondrial deoxynucleotide pools is essential for synthesis. Mutations in eight nuclear genes—POLG, TK2, DGUOK, SUCLA2, SUCLG1, C10orf2, RRM2B, and MPV17—have been reported to cause depletion of mtDNA in some or more tissues. The first seven genes are involved in metabolism. Biochemical imbalance in the nucleotide pools results in defects in mtDNA synthesis. MPV17 encodes an inner mitochondrial protein of unknown function.
The clinical is widely variable. Three well-established forms are known: myopathic, encephalomyopathic, and hepatocerebral. In the myopathic form, onset is in the first year of life with hypotonia, weakness, and ophthalmoplegia. Death occurs in infancy or childhood, but some patients live longer. A milder myopathic form with longer survival and muscle weakness with encephalopathy and seizures has been described. Mutations in the TK2 gene are found in 20 percent of the myopathic cases. Muscle histochemistry shows deficiency of cytochrome c oxidase of the respiratory chain. Biochemical analysis reveals defects in respiratory chain enzymes.
The encephalomyopathic form is characterized by high blood lactate, severe psychomotor disability with muscle hypotonia, hearing impairment, generalized seizures, contractures, finger dystonia, and mild ptosis. Mutations in SUCLA2 in the muscle and nervous system affect these tissues specifically. Another form is due to mutations in SUCLG1, which is expressed ubiquitously and therefore is associated with muscle, liver, and nervous system involvement.
In the hepatocerebral form, onset is between birth and six months. Degeneration of the liver and progressive neurological symptoms are associated with POLG1 mutations. Respiratory chain deficiency in the liver is found in some cases. In a few patients, mutations in DGUOK and MPV17 are reported.
Hepatocerebral MDS also includes a wide range of diseases such as Alpers-Huttenlocher hepatopathic poliodystrophy, SANDO, and SCAE, which are associated with mutations in POLG1. Liver dysfunction is severe and progressive, with sensory ataxic syndromes with or without epilepsy.
Mutations in RRM2B have been reported in infants who presented with hypotonia, tubulopathy, seizures, respiratory distress, diarrhea, and lactic acidosis. MDS is a heterogenous group of diseases, the pathogenic mechanism of which is not clear.
Symptoms
Severe hepatic failure with hypotonia leading to death before one year of age is observed in the hepatocerebral form of MDS. In the myopathic form, progressive muscle weakness, mental retardation, encephalopathy, and renal dysfunction have been reported. In late-onset cases, hypotonia, nonprogressive weakness, and neuropathy are the main clinical symptoms.
Screening and Diagnosis
Low mtDNA/nuclear DNA ratios in affected tissues by quantitative PCR or Southern blotting, tissue histochemistry, and low activities of respiratory chain enzymes confirm diagnosis of MDS. Mutation analysis of patients and parents for the eight known genes that cause MDS will establish the genetic diagnosis. Histochemical analysis of affected tissues is available in specific centers.
Treatment and Therapy
Treatments are aimed to alleviate symptoms or slow the progress of the disease. In the case of Alpers-Huttenlocher, treatment with valproate to control seizures will lead to fatal liver failure and should be avoided. Some aggressive treatments include liver transplantation and allogeneic stem cell transplantation. Experimental therapies include small molecule substrate enhancement and specialized gene therapy. In 2024, researchers successfully began to utilize nucleoside supplements as treatments for MDS. Despite this progress, no curative treatment was available.
Prevention and Outcomes
Identification of mutations in several genes that cause MDS makes prenatal diagnosis possible in affected families. Genetic counseling may be useful in these cases, but should be done with caution. In the MDS cases with no known genetic defects, prenatal diagnosis is not possible.
Bibliography
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