Mitochondrial DNA Depletion Syndrome 13 (Encephalomyopathic Type)

Alternative Names

  • MTDPS13
  • Mitochondrial DNA Depletion Syndrome, Encephalomyopathic Form with Variable Craniofacial Anomalies
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WHO-ICD-10 version:2010

Diseases of the nervous system

Diseases of myoneural junction and muscle

OMIM Number

615471

Mode of Inheritance

Autosomal recessive

Gene Map Locus

6q16.1-q16.2

Description

MTDPS13 is a disorder characterized by mitochondrial respiratory chain defects and the depletion of mtDNA.  Patients also exhibit fragmentation of the mitochondrial network and increased serum lactate, ammonia and alanine.  The disorder results in encephalopathy, cerebral atrophy, leukodystrophy, white matter abnormalities, hypotonia, ataxia, seizures, gastroesophageal reflux disease, and muscle atrophy.  Affected individuals also suffer from severe global developmental delay and a failure to thrive.  Patients may display variable facial dysmorphia such as a narrow elongated face, protruding malformed ears, epicanthal folds and downslanting palpebral fissures of the eyes with thick eyebrows, a saddle nose, and an everted lower lip.  Other less common features in MTDPS13 include microcephaly, plagiocephaly, cataracts, scoliosis, neutropenia, and recurrent infections.  Similarly to other encephalomyopathic forms of mtDNA depletion syndromes, MTDPS13 is a severe disorder and may result in early lethality. Its onset is typicallyat birth or in early infancy. The disease does not appear to have a gender bias.However, the disorder does appear to have a racial predisposition, with most reported cases occurring in Arab families.

Diagnosis can be made based on laboratory analysis of mitochondrial respiratory chain defects and serum lactate levels as well as by genetic testing.  Currently, there is no cure for the disorder and treatment is focused on supportive care. 

Molecular Genetics

MTDPS13 follows an autosomal recessive pattern of inheritance and is caused by homozygous mutations in the FBXL4 gene.  This gene encodes an F-box protein that forms a component of a modular E3 ubiquitin protein ligase involved in phosphorylation dependent ubiquitination.  So far about five different variants have been identified in the gene, resulting in amino acid substitutions or premature truncation.  It has been found that expression of wildtype FBXL4 in the cells of individuals affected by MTDPS13 results in the rescue of mitochondrial biochemical defects and mtDNA depletion.

Epidemiology in the Arab World

View Map
Subject IDCountrySexFamily HistoryParental ConsanguinityHPO TermsVariantZygosityMode of InheritanceReferenceRemarks
615471.1.1United Arab EmiratesYesYesNM_012160.4:c.1304G>THomozygousAutosomal, RecessiveAl-Shamsi et al. 2016 Patient with mitocho...
615471.1.2United Arab EmiratesYesYesNM_012160.4:c.1304G>THomozygousAutosomal, RecessiveAl-Shamsi et al. 2016 Sibling of 615471.1....
615471.2United Arab EmiratesYes Developmental regression; Hypotonia; ...NM_012160.4:c.1067delHomozygousAutosomal, RecessiveAl-Shamsi et al. 2016 Three siblings died ...
615471.3.1LebanonFemaleYes Neurodevelopmental delay; Generalized h...NM_012160.4:c.1303C>THomozygousAutosomal, RecessiveBallout et al. 2019
615471.4United Arab EmiratesFemale Metabolic acidosis; Failure to thrive; G...NM_012160.4:c.1304G>THomozygousAutosomal, RecessiveHuemer et al. 2015
615471.5Saudi ArabiaMaleYes Global developmental delay; Delayed spee...NM_001278716.2:c.1703G>CHomozygousAutosomal, RecessiveGai et al. 2013
615471.6.1Saudi ArabiaMaleYesYes Global developmental delay; Lactic acido...NM_001278716.2:c.1444C>THomozygousAutosomal, RecessiveAlazami et al. 2015; Gai et al. 2013
615471.6.2Saudi ArabiaMaleYesYes Global developmental delay; Lactic acido...NM_001278716.2:c.1444C>THomozygousAutosomal, RecessiveGai et al. 2013 Sibling of 615471.6....
615471.6.3Saudi ArabiaMaleYesYes Global developmental delay; Lactic acido...NM_001278716.2:c.1444C>THomozygousAutosomal, RecessiveGai et al. 2013 Sibling of 615471.6....
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