SLC25A42‐associated mitochondrial encephalomyopathy: Report of additional founder cases and functional characterization of a novel deletion

Abstract

SLC25A42 is the main transporter of coenzyme A (CoA) into mitochondria. To date, 15 individuals have been reported to have one of two bi‐allelic homozygous missense variants in the SLC25A42 as the cause of mitochondrial encephalomyopathy, of which 14 of them were of Saudi origin and share the same founder variant, c.871A > G:p.Asn291Asp. The other subject was of German origin with a variant at canonical splice site, c.380 + 2 T > A. Here, we describe the clinical manifestations and the disease course in additional six Saudi patients from four unrelated consanguineous families. While five patients have the Saudi founder p.Asn291Asp variant, one subject has a novel deletion. Functional analyses on fibroblasts obtained from this patient revealed that the deletion causes significant decrease in mitochondrial oxygen consumption and ATP production compared to healthy individuals. Moreover, extracellular acidification rate revealed significantly reduced glycolysis, glycolytic capacity, and glycolytic reserve as compared to control individuals. There were no changes in the mitochondrial DNA (mtDNA) content of patient fibroblasts. Immunoblotting experiments revealed significantly diminished protein expression due to the deletion. In conclusion, we report additional patients with SLC25A42‐associated mitochondrial encephalomyopathy. Our study expands the molecular spectrum of this condition and provides further evidence of mitochondrial dysfunction as a central cause of pathology. We therefore propose that this disorder should be included in the differential diagnosis of any patient with an unexplained motor and speech delay, recurrent encephalopathy with metabolic acidosis, intermittent or persistent dystonia, lactic acidosis, basal ganglia lesions and, especially, of Arab ethnicity. Finally, deep brain stimulation should be considered in the management of patients with life altering dystonia.

A Novel GEMIN4 Variant in a Consanguineous Family Leads to Neurodevelopmental Impairment with Severe Microcephaly, Spastic Quadriplegia, Epilepsy, and Cataracts

“…We performed WES to identify plausible disease-causing variant(s). Our analysis, coupled with previously published variant filtering processes [ 30 , 31 , 32 , 33 , 34 ], yielded a novel homozygous missense variant in exon 2 of GEMIN4 (NM_015721: c.440A>G:p.His147Arg) as the only candidate underlying the disease. Then we used Sanger sequencing for the segregation analysis and confirmation of the variant in the family.…”

Application of deep brain stimulation for the treatment of childhood-onset dystonia in patients with MEPAN syndrome

“…Although there are no current reports of neuromodulatory intervention in children with MEPAN syndrome, the efficacy of GPi-DBS has been reported for movement disorders in other degenerative neurometabolic conditions such as PKAN and mitochondrial disorders ( 19 , 26 , 46–48 ). GPi-DBS showed moderate efficacy in atypical PKAN, variable benefits in typical PKAN ( 19 ), and mixed effects in mitochondrial disease ( 26 , 46–48 ). However, GPi-DBS may be less effective in cases of dystonia that present with structural abnormalities and will not affect the progression of the underlying metabolic condition.…”

Heteroplasmic pathogenic m.12315G>A variant in MT‐TL2 presenting with MELAS syndrome and depletion of nitric oxide donors

“…CMA revealed a 1.16 Mb deletion at 16p13.11 [15126709–16286722] which has been associated with intellectual disability, epilepsy, and microcephaly with incomplete penetrance (Nagamani et al, 2011). WES revealed biallelic variants of uncertain significance in SLC6A20 (c.1303+4A>G; c.1732T>G) which is not known to be associated with human disease, and a heterozygous single‐nucleotide variant of uncertain significance in SLC25A42 (MIM: 618416) (c.676C>T) that is associated with an autosomal recessively inherited form of neurological regression and metabolic crises (Aldosary et al, 2021). Pantothenic acid 500 mg two times daily and riboflavin 100 mg two times daily were started and biotin and thiamine were stopped after WES resulted due to the concern that SLC25A42 explained the clinical presentation and an intronic variant may be present on the second allele.…”