Mitochondrial DNA depletion syndrome 13

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Description from OMIM

Mitochondrial DNA depletion syndrome-13 is an autosomal recessive disorder characterized by early infantile onset of encephalopathy, hypotonia, lactic acidosis, and severe global developmental delay. Cells derived from patient tissues show defects in mitochondrial oxidative phosphorylation and decreased mtDNA content (summary by Bonnen et al., 2013 and Gai et al., 2013). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).

Prevalence of clinical parameters (%)

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Number of patients in the reference Percent affected patients (Between 0 and 1, eg. 0.1 = 10%)
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List of symptoms

Symptom/sign Organ system Percent affected Pubmed id Added on(yyyy-mm-dd) Edit/add reference
Intrauterine growth retardation multi 100 % 23993194 2014-04-25
Developmental delay nervous 100 % 23993194 2014-04-25
Lactate accumulation circulatory 100 % 23993194 2014-04-25
Leukodystrophy nervous 100 % 23993194 2014-04-25
Hypotonia nervous 100 % 23993194 2014-04-25
Muscle atrophy skeletal 100 % 23993194 2014-04-25
Myopathy skeletal 100 % 23993194 2014-04-25
Dysphagia nervous 88 % 23993194 2014-04-25
Cerebral atrophy nervous 86 % 23993194 2014-04-25
Seizures nervous 78 % 23993194 2014-04-25
Failure to thrive multi 63 % 23993194 2014-04-25
Basal ganglia pathology nervous 57 % 23993194 2014-04-25
Facial dysmorphism skeletal 56 % 23993194 2014-04-25
Ataxia nervous 43 % 23993194 2014-04-25
Dystonia nervous 33 % 23993194 2014-04-25

List of references:

Mutations in FBXL4, encoding a mitochondrial protein, cause early-onset mitochondrial encephalomyopathy.
Xiaowu Gai, Daniele Ghezzi, Mark A Johnson, Caroline A Biagosch, Hanan E Shamseldin, Tobias B Haack, Aurelio Reyes, Mai Tsukikawa, Claire A Sheldon, Satish Srinivasan, Matteo Gorza, Laura S Kremer, Thomas Wieland, Tim M Strom, Erzsebet Polyak, Emily Place, Mark Consugar, Julian Ostrovsky, Sara Vidoni, Alan J Robinson, Lee-Jun Wong, Neal Sondheimer, Mustafa A Salih, Emtethal Al-Jishi, Christopher P Raab, Charles Bean, Francesca Furlan, Rossella Parini, Costanza Lamperti, Johannes A Mayr, Vassiliki Konstantopoulou, Martina Huemer, Eric A Pierce, Thomas Meitinger, Peter Freisinger, Wolfgang Sperl, Holger Prokisch, Fowzan S Alkuraya, Marni J Falk, Massimo Zeviani,

Whole-exome sequencing and autozygosity mapping studies, independently performed in subjects with defective combined mitochondrial OXPHOS-enzyme deficiencies, identified a total of nine disease-segregating FBXL4 mutations in seven unrelated mitochondrial disease families, composed of six singletons and three siblings. All subjects manifested early-onset lactic acidemia, hypotonia, and developmental delay caused by severe encephalomyopathy consistently associated with progressive cerebral atrophy and variable involvement of the white matter, deep gray nuclei, and brainstem structures. A wide range of other multisystem features were variably seen, including dysmorphism, skeletal abnormalities, poor growth, gastrointestinal dysmotility, renal tubular acidosis, seizures, and episodic metabolic failure. Mitochondrial respiratory chain deficiency was present in muscle or fibroblasts of all tested individuals, together with markedly reduced oxygen consumption rate and hyperfragmentation of the mitochondrial network in cultured cells. In muscle and fibroblasts from several subjects, substantially decreased mtDNA content was observed. FBXL4 is a member of the F-box family of proteins, some of which are involved in phosphorylation-dependent ubiquitination and/or G protein receptor coupling. We also demonstrate that FBXL4 is targeted to mitochondria and localizes in the intermembrane space, where it participates in an approximately 400 kDa protein complex. These data strongly support a role for FBXL4 in controlling bioenergetic homeostasis and mtDNA maintenance. FBXL4 mutations are a recurrent cause of mitochondrial encephalomyopathy onset in early infancy.

American journal of human genetics - Sep 2013