Mitochondrial DNA depletion syndrome-4B is an autosomal recessive progressive multisystem disorder clinically characterized by chronic gastrointestinal dysmotility and pseudoobstruction, cachexia, progressive external ophthalmoplegia (PEO), axonal sensory ataxic neuropathy, and muscle weakness (van Goethem et al., 2003).
... Mitochondrial DNA depletion syndrome-4B is an autosomal recessive progressive multisystem disorder clinically characterized by chronic gastrointestinal dysmotility and pseudoobstruction, cachexia, progressive external ophthalmoplegia (PEO), axonal sensory ataxic neuropathy, and muscle weakness (van Goethem et al., 2003). For a discussion of genetic heterogeneity of autosomal recessive mtDNA depletion syndromes, see MTDPS1 (603041).
Vissing et al. (2002) reported 2 sisters who presented at age 15 years with unsteady gait and gastrointestinal malabsorption. Other features included neurogenic changes on EMG, peripheral neuropathy, ophthalmoplegia, and diffuse muscle weakness. The disorder was indistinguishable from ... Vissing et al. (2002) reported 2 sisters who presented at age 15 years with unsteady gait and gastrointestinal malabsorption. Other features included neurogenic changes on EMG, peripheral neuropathy, ophthalmoplegia, and diffuse muscle weakness. The disorder was indistinguishable from that known as mitochondrial gastrointestinal encephalopathy (MNGIE) due to mutation in the TYMP gene (131222), except for absence of leukoencephalopathy on MRI and mildly reduced thymidine phosphorylase activity (42% of control). In addition, no mutation in the TYMP or the DNT2 (605292) gene was found in 1 of the patients. Vissing et al. (2002) suggested that the condition may be due to a nuclear gene mutation causing a defect in intergenomic signaling. Van Goethem et al. (2003) provided a follow-up of the patients reported by Vissing et al. (2002). Features included chronic gastrointestinal pseudoobstruction, PEO, axonal sensory ataxic neuropathy, muscle weakness, and cachexia. Brain MRI was normal. Muscle biopsy demonstrated few ragged-red fibers, cytochrome c oxidase negative fibers, decreased enzymatic activities of respiratory chain complexes I and IV, depletion of mtDNA, and multiple mtDNA deletions. Giordano et al. (2009) reported a newborn boy with congenital myopathy and gastrointestinal pseudoobstruction due to compound heterozygous mutations in the POLG gene (174763.0006 and 174763.0021). He presented with severe hypotonia and generalized muscle weakness, requiring ventilatory assistance and total parenteral nutrition. Hearing loss was detected by auditory evoked potentials, and brain MRI showed mildly enlarged ventricles, but leukoencephalopathy was not noted. He also developed severe abdominal distention with a hypoactive bowel. MRI revealed marked intestinal dilation without mechanical obstruction. Other features included low-set ears, hearing loss, and bilateral clubfoot. Laboratory studies showed hypoglycemia, hypomagnesemia, and hypokalemia; lactate was normal, and liver enzymes were unremarkable. Skeletal muscle biopsy showed scattered, hypertrophic COX-deficient fibers, and there was marked mtDNA depletion in muscle (93% decrease compared to controls). The patient died at age 20 days from respiratory failure. There was no liver damage aside from that resulting from parenteral nutrition. Analysis of the bowel showed that mtDNA depletion was confined mainly to the external layer of the muscularis propria. Kurt et al. (2010) reported 2 unrelated patients, a girl and a boy, with mtDNA depletion associated with features of MNGIE and of Alpers syndrome with hepatic involvement (MTDPS4A; 203700). Both had compound heterozygous mutations in the POLG gene (P1073L (174763.0022) in both, and A467T (174763.0002) and G848S (174763.0006), respectively). Both patients showed developmental delay. The girl was hypotonic at birth, and later had short stature, neurosensory hearing loss, celiac disease, liver dysfunction with hepatic fibrosis, and gastrointestinal pseudoobstruction with dysmotility. Brain MRI showed signal abnormalities in the basal ganglia and thalami. She died at age 9 years. RT-PCR showed severe mtDNA depletion in liver tissue (72.1% depletion compared to controls). The boy had poor growth, hypotonia, seizures, and intestinal hypomotility, and died at age 10 months. Muscle tissue showed mtDNA depletion (64%). Kurt et al. (2010) emphasized the phenotypic variability associated with recessive POLG mutations, and noted that various signs and symptoms can occur.
In 2 sisters with features of MNGIE but no leukoencephalopathy in whom no mutations were found in the TYMP gene by Vissing et al. (2002), Van Goethem et al. (2003) identified compound heterozygosity for 3 mutations in the ... In 2 sisters with features of MNGIE but no leukoencephalopathy in whom no mutations were found in the TYMP gene by Vissing et al. (2002), Van Goethem et al. (2003) identified compound heterozygosity for 3 mutations in the POLG gene: T251I (174763.0007) and P587L (174763.0011), which were in cis on the same allele, and N864S (174763.0012), which was in trans.