Long-term survival in a child with severe encephalopathy, multiple respiratory chain deficiency and GFM1 mutations

Abstract

Background: Mitochondrial diseases due to deficiencies in the mitochondrial oxidative phosphorylation system (OXPHOS) can be associated with nuclear genes involved in mitochondrial translation, causing heterogeneous early onset and often fatal phenotypes.Case report: The authors describe the clinical features and diagnostic workup of an infant who presented with an early onset severe encephalopathy, spastic-dystonic tetraparesis, failure to thrive, seizures and persistent lactic acidemia. Brain imaging revealed thinning of the corpus callosum and diffuse alteration of white matter signal. Genetic investigation confirmed two novel mutations in the GFM1 gene, encoding the mitochondrial translation elongation factor G1 (mtEFG1), resulting in combined deficiencies of OXPHOS.Discussion: The patient shares multiple clinical, laboratory and radiological similarities with the 11 reported patients with mutations involving this gene, but presents with a stable clinical course without metabolic decompensations, rather than a rapidly progressive fatal course. Defects in GFM1 gene confer high susceptibility to neurologic or hepatic dysfunction and this is, to the best of our knowledge, the first described patient who has survived beyond early childhood. Reporting of such cases is essential so as to delineate the key clinical and neuroradiological features of this disease and provide a more comprehensive view of its prognosis.

Clinical, neuroimaging and biochemical findings in patients and patient fibroblasts expressing ten novel GFM1 mutations

“…Using targeted exome sequencing (see supplemental information) we identified compound heterozygous or homozygous GFM1 variants in all nine patients. Two of the variants, NM_024996.5:c.2011C>T p.(Arg671Cys) in patients 1, 2, 5, 6, 8, and 9 and NM_024996.5: c.1404del p.(Gly469Valfs*84) in patient 2 were previously reported (Brito et al, ; Calvo et al, ; Galmiche et al, ). Ten variants were identified for the first time (Figures a and a and Table S2) and include six, predictably pathogenic, missense mutations affecting evolutionary conserved amino acids NM_024996.5:c.958C>G p.(Pro320Ala); NM_024996.5:c.1922C>A p.(Ala641Glu); NM_024996.5:c.248A>T p.(Asp83Val); NM_024996.5:c.1546T>C p.(Cys516Arg); NM_024996.5:c.1571C>T p.(Ala524Val) and NM_024996.5:c.1822C>T p.(Arg608Trp) in patients 3, 4, 5, 7, and 9; one nonsense mutation, NM_024996.5:c.100C>T p.(Arg34*), in patient 6, leading to a premature stop codon in the mitochondrial targeting sequence of EFG1; one frameshift mutation causing a premature stop codon, NM_024996.5:c.1297_1300del p.(Asp433Lysfs*20) in patient 1; one deletion of four amino acids, NM_024996.5:c.1149_1160del p.(Ile384_Thr387del) in patient 4; and an intragenic duplication in patient 7.…”

“…Liver disease, previously proposed as one of the major clinical presentations of GFM1 mutations, was observed only in two patients one of which died at 3 years of age due to acute liver failure. Most patients presented a stable clinical course during the follow‐up period seen only in two previous cases of GFM1 mutations (Brito et al, ; Simon et al, ). Our work expands the genetic spectrum of GFM1 ‐linked disease and demonstrates that neurological involvement is the predominant clinical presentation, which can be frequently associated with prolonged survival.…”

“…However, it should be noted that the follow‐up was not detailed for four patients (Calvo et al, ; Galmiche et al, ; Kohda et al, ). Previously, Brito et al () and Simon et al () reported two patients with a stable clinical course, prompting the latter to suggest that survival of GFM1 patients through an early‐age vulnerability phase lets the disease settle into a more stable clinical course. What promotes such survival remains unclear—especially, because the sibling of the surviving patient in the Simon et al report died at 10 months of age—but our report indicates that, indeed, stable clinical course and long‐term survival are more common than previously thought to brighten the formerly bleak prognosis for the outcome of GFM1 ‐linked disease.…”

Activation of a cryptic splice site in the mitochondrial elongation factor GFM1 causes combined OXPHOS deficiency

“…Prognosis for patients with GFM1 mutations is strikingly poor, as all patients died in infancy, with the exception of one milder case reported to be alive at 6 years of age (Brito et al, 2015). This patient’s mild case could not be explained by mutation type since she is compound heterozygous for one nonsense and a previously reported severe missense mutation.…”

Periventricular Calcification, Abnormal Pterins and Dry Thickened Skin: Expanding the Clinical Spectrum of RMND1?

“…Cell lysates were prepared from patient fibroblasts (II:1) and analysed by Western blotting as previously described (Brito et al 2015). Antibodies against RMND1 (Sigma HPA031399), NDUFB8 (Abcam ab110242), SDHA (Abcam ab14715), UQCRC2 (Abcam ab14745), COXI (Abcam ab14705), COXII (Abcam ab110258), ATP5A (ab14748) and VDAC1 (Abcam ab14734) were used, followed by HRP-conjugated secondary antibodies (DakoCytomation).…”