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CASE REPORT
Ahead of print publication
 

Clinical phenotype of FASTKD2 mutation


 Child Neurology and Epilepsy Center, Surat, Gujarat, India

Date of Submission25-Jul-2020
Date of Decision03-Oct-2020
Date of Acceptance28-Mar-2021
Date of Web Publication11-Oct-2021

Correspondence Address:
Seema Balasubramaniam,
Clinical Extern, Child Neurology and Epilepsy Center, 4th Floor, Sangini Square Near Kashi Plaza, Majura gate, Surat 395002, Gujarat.
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jpn.JPN_199_20

 

   Abstract 

Mitochondrial disorders (MIDs) are frequently multisystemic in nature and cause significant morbidity and mortality. Accurate assessment of mitochondrial disease prevalence has been difficult in the past. Primary MIDs are due to mutations in mitochondrial DNA (mtDNA) or nuclear DNA (nDNA)-located genes. Here we report cases of two siblings who presented to the pediatric emergency department with status epilepticus. Initially, the elder sibling was treated for metabolic encephalopathy and viral encephalitis, during his admission to the hospital. On treatment with multiple antiepileptic drugs, the status epilepticus subsided. A provisional diagnosis of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes was made. Magnetic resonance imaging showed diffusion restriction in the left temporal lobe, insular cortex, and left lentiform nucleus, which completely resolved on follow-up after 1 month. His sudden demise in May 2019 due to status epilepticus, and a similar case presentation in his younger sibling, prompted us to do a genetic analysis test. The exome sequence revealed FASTKD2 mutation, a rare variant. This case report helps in increasing the awareness among the clinicians about the clinical presentation of FASTKD2 mutation case.


Keywords: FASTKD2 mutation, MELAS, status epilepticus



How to cite this URL:
Shah R, Balasubramaniam S. Clinical phenotype of FASTKD2 mutation. J Pediatr Neurosci [Epub ahead of print] [cited 2021 Nov 28]. Available from: https://www.pediatricneurosciences.com/preprintarticle.asp?id=327892





   Introduction Top


Mitochondrial disorders (MIDs) are clinical phenotypes associated with abnormalities of the terminal component of aerobic energy metabolism, i.e., oxidative phosphorylation (OXPHOS), a complex pathway linking cellular respiration to adenosine triphosphate (ATP) synthesis. OXPHOS is carried out in the inner mitochondrial membrane by the mitochondrial respiratory chain.[1]

MIDs are frequently multisystemic in nature and cause significant morbidity and mortality. Accurate assessment of mitochondrial disease prevalence has been difficult in the past.[2] The majority of mitochondrial proteins are encoded by nuclear DNA (nDNA), but 13 are encoded by mitochondrial DNA (mtDNA); consequently, mitochondria are under the dual genetic control of both the mitochondrial and nuclear genomes. Reflecting their diverse functions, only 150 mitochondrial proteins are directly involved in OXPHOS and ATP production.[3] Primary MIDs are due to mutations in mtDNA or nDNA-located genes that encode subunits of respiratory chain complexes, assembly factors (ancillary proteins), proteins involved in mtDNA maintenance (intergenomic signaling), in the mitochondrial protein synthesis machinery, in coenzyme Q generation, in the mitochondrial transport machinery, or in apoptosis.[4] Electron transport chain is a dedicated transcription and translation machinery to synthesize a subset of the membrane proteins in the mitochondria. Defects of mitochondrial respiration are associated with a wide spectrum of clinical manifestations and, given the dual genetic origin of the components of the electron transport chain, elucidating their molecular causes often is not straightforward.[5]

In addition to mutations in genes encoding OXPHOS components, including complexes I, II, III, IV, and V, mutations in several other genes related to OXPHOS integrity, such as OXPHOS assembly, mtDNA maintenance, and mitochondrial RNA (mtRNA) translation, were identified in patients with mitochondrial diseases.[6] Isolated complex IV (cytochrome c oxidase) deficiency is one of the most frequent respiratory chain defects in MIDs and usually occurs together with severe pediatric or rarely adult multisystem disease.[7] FAST kinase domain-containing protein (FASTKD) is a group of six proteins containing the FAST kinase domain.[6] Because nuclear genes coding for assembly factors of cytochrome c oxidase (COX), such as SURF-1, are known to cause complex IV deficiency, a role for FASTKD2 in COX assembly has been evaluated by blue-native gel electrophoresis (BNGE)-western-blot analysis. Mutations within dozens of the RNA-binding proteins detected by interactome capture, including FASTKD2 (FAS-induced serine/threonine kinase domain containing protein 2), which lacks canonical RNA-binding domains, have been associated with Mendelian diseases. Mutated FASTKD2 has been identified as the likely cause of an atypical form of infantile mitochondrial encephalomyopathy in a consanguineous family of Bedouin origin.[1]

Loss of FASTKD2 was shown to result in a significant decrease in mtRNA and compromised mitochondrial respiration owing to impairment of the activity of mitochondrial complexes I, III, IV, and V.[5]

We report a case of FASTKD2 gene mutation presenting with mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes (MELAS)-like symptoms in pediatric patients presenting with status epilepticus in childhood.


   Case History Top


Here we present the cases of two siblings with similar chief complaints.

The elder sibling, an issue of non-consanguineous marriage, presented to the pediatrics emergency department at 2½ years of age in July 2008 with fever, left focal status epilepticus, and vomiting which turned into epilepsia partialis continua. He was then admitted to the hospital for 15–20 days and treated for metabolic encephalopathy/viral encephalitis. Arterial blood gas analysis revealed acidosis. His status was controlled with multiple anti-epileptic drugs; thereafter he had a good recovery but reported decreased use of right upper and lower limbs was noted. Magnetic resonance imaging (MRI) findings were suggestive of diffusion restriction in the left temporal lobe, insular cortex, and left lentiform nucleus, which completely resolved on follow-up after 1 month.

His pre-illness language skills were delayed, which did not deteriorate further. His cognitive skills remained unchanged, as was deduced at the age of 2½ years (IQ was not formally assessed). Over the last 11 years, the patient had been relatively stable, with well-controlled seizures and tremors of the right upper limb until his demise at the age of 14 years in May 2019 due to an episode of status epilepticus.

His younger sibling, aged 9 years, also has a similar history. At the age of 3½ years in July 2014, he was admitted to the hospital for fever, vomiting, and left focal status epilepticus. After 20 days of hospitalization, the patient had a good recovery with no new episodes of seizures and no complaints of hemiparesis. Prior to admission, his speech and cognitive skills were delayed and displayed marginal improvement but not at par with normal children of the similar age group.

In May 2020, the patient presented to the emergency department with right focal status epilepticus. The patient was treated with multiple anti-epileptic drugs and the status was controlled. His arterial blood gas analysis revealed acidosis. MRI findings were suggestive of abnormal areas of diffusion restriction in the left high frontal, parietal, posteromedial temporal cortex, left occipital lobe, and posterolateral thalamus [Figure 1][Figure 2][Figure 3].
Figure 1: MRI showing diffusion restriction in left posteromedial parietal cortex

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Figure 2: MRI showing diffusion restriction in the left occipital lobe

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Figure 3: Flair MR showing diffusion restriction in the left posterolateral thalamus

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After discharge, the patient has been prescribed multiple anti-epileptic drugs (topiramate, levetiracetam, and clobazam).

In view of the similar presentation in both the siblings, diffusion restriction areas reported on the MRI, and lactic acidosis on arterial blood gas samples, we suspected MELAS. However, due to various atypical features, which were not consistent with MELAS, we decided to do a genetic test and sent blood samples for both whole mitochondrial genome and clinical exome sequencing. Though pathogenic variants were not detected on mitochondrial genome sequencing, clinical exome sequencing revealed significant results. In this test, selective capture and sequencing of the protein coding regions of the genome/genes are performed. DNA extracted from blood was used to perform targeted gene capture using a custom capture kit. Mutations identified in the exonic regions are generally actionable compared to variations that occur in non-coding regions. A homozygous 3′ splice site variation in intron 4 of the FASTKD2 gene (chr2:g.206771892A>G; Depth:81x) that affects the invariant AG acceptor splice site upstream of exon 5 (c.991-2A>G; ENST00000402774.8) was detected. The variant has not been reported in the 1000 genomes database and has a minor allele frequency [Figure 4].
Figure 4: Clinical exome sequence report

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   Discussion Top


Mitochondrial encephalomyopathy with developmental delay, hemiplegia, convulsions, asymmetrical brain atrophy, and low COX activity in skeletal muscle was reported in patients with mutations in FASTKD2, encoding the fas-activated serine-threonine kinase domain 2 protein.[1],[8],[9] The molecular understanding of FASTKD2 action has remained unexplored for several years but was addressed later by the independent work of few research teams.[10]

Although FASTKD2 is not directly involved in COX assembly, its ablation is indeed associated with COX deficiency in skeletal muscle. The elucidation of the function of FASTKD2 is made difficult by the likely rarity of the clinical condition linked to its disruption and by the difficulty to establish cell lines stable expressing recombinant FASTKD2HA.[1] Genomic deletion of FASTKD2 by CRISPR-mediated mutagenesis impairs global mitochondrial translation to an even greater extent than RNAi-mediated depletion, thus confirming the importance of the protein for mitochondrial protein synthesis.[5]

The effects of FASTKD2 deficiency appear to be cell type- and tissue-specific, as the originally reported complex IV deficiency was only detectable in muscle biopsies but not in fibroblasts of the affected patients.[1]

Taken together, we believe that patients with mutations in FASTKD2 can show high clinical and molecular heterogeneity. The combined use of clinical and molecular diagnoses is recommended for the diagnosis of FASTKD2 mutation-related mitochondrial diseases.[6]

Meticulous clinical and biochemical characterization of patients remains fundamental to diagnostic yield. Unfortunately, to date, there are few effective treatments and no known cure.


   Conclusion Top


The aim of this case report is to increase awareness among clinicians about the clinical presentation and understanding of FASTKD2 mutation case. This will enable early recognition of the disorder, thereby improving the quality of the life in patients and their families.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

1.
Ghezzi D, Saada A, D’Adamo P, Fernandez-Vizarra E, Gasparini P, Tiranti V, et al. FASTKD2 nonsense mutation in an infantile mitochondrial encephalomyopathy associated with cytochrome c oxidase deficiency. Am J Hum Genet 2008;83:415-23.  Back to cited text no. 1
    
2.
Gorman GS, Schaefer AM, Ng Y, Gomez N, Blakely EL, Alston CL, et al. Prevalence of nuclear and mitochondrial DNA mutations related to adult mitochondrial disease. Ann Neurol 2015;77:753-9.  Back to cited text no. 2
    
3.
Craven L, Alston CL, Taylor RW, Turnbull DM. Recent advances in mitochondrial disease. Annu Rev Genomics Hum Genet 2017;18:257-75.  Back to cited text no. 3
    
4.
Finsterer J, Kovacs GG, Rauschka H, Ahting U. Adult, isolated respiratory chain complex IV deficiency with minimal manifestations. Folia Neuropathol 2015;53: 153-7.  Back to cited text no. 4
    
5.
Popow J, Alleaume AM, Curk T, Schwarzl T, Sauer S, Hentze MW. FASTKD2 is an RNA-binding protein required for mitochondrial RNA processing and translation. RNA 2015;21:1873-84.  Back to cited text no. 5
    
6.
Wei X, Du M, Li D, Wen S, Xie J, Li Y, et al. Mutations in FASTKD2 are associated with mitochondrial disease with multi-OXPHOS deficiency. Hum Mutat 2020;41:961-72.  Back to cited text no. 6
    
7.
Finsterer J, Kovacs GG, Rauschka H, Ahting U. Adult, isolated respiratory chain complex IV deficiency with minimal manifestations. Folia Neuropathol 2015;53:153-7.  Back to cited text no. 7
    
8.
Rahman S. Mitochondrial disease and epilepsy. Dev Med Child Neurol 2012;54:397-406.  Back to cited text no. 8
    
9.
Boczonadi V, Ricci G, Horvath R. Mitochondrial DNA transcription and translation: Clinical syndromes. Essays Biochem 2018;62:321-40.  Back to cited text no. 9
    
10.
Jourdain AA, Popow J, de la Fuente MA, Martinou JC, Anderson P, Simarro M. The FASTK family of proteins: Emerging regulators of mitochondrial RNA biology. Nucleic Acids Res 2017;45:10941-7.  Back to cited text no. 10
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]



 

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