2.1.6 Progressive microcephaly with seizures and cerebral and cerebellar atrophy (MSCCA; 615760)

Zhang et al. [19] in four patients from two unrelated families with progressive microcephaly, intractable seizures, and cerebral and cerebellar atrophy (MSCCA; 615,760) identified compound heterozygous mutations in the QARS gene (603727.0001–603727.0004). The mutations were found by whole-exome sequencing and confirmed by Sanger sequencing. QARS (or GLnRS; 603,727) is a class I aminoacyl-tRNA synthetase. Aminoacyl-tRNA synthetases are enzymes that charge tRNAs with their cognate amino acids. The specificity of this reaction determines the fidelity of mRNA translation. At least one synthetase exists in the cytoplasm for each amino acid. QARS is essential for normal brain development. Studies in patient cells and expression of recombinant variants in E. coli showed that all four mutations caused a severe loss of QARS catalytic activity, consistent with a loss-offunction effect. Homozygous loss of QARS in zebrafish caused decreased brain and eye size and extensive cell death in the brain. Two sibs observed by Zhang et al. [19], born of unrelated French parents, had clinical and EEG signs of malignant migrating partial seizures of infancy and compound heterozygous mutations in the QARS gene, a c.169 T-C transition, resulting in a tyr57-to-his (603727.0003) substitution at a highly conserved residue in the N-terminal domain, and a c.1543C-T transition, resulting in an arg515-to-trp (603727.0004) substitution at a highly conserved residue in the catalytic domain. Patient cells showed decreased aminoacylation activity of QARS compared to control. Expression of recombinant arg515trp (.0004) in E. coli resulted in no QARS catalytic activity, whereas tyr57his (.0003) decreased QARS activity to less than 10% that of controls. In addition, the arg515trp mutation appeared to cause protein misfolding and aggregation, resulting in decreased expression of the soluble mutant protein [19].

### 2.1.7 Rhizomelic chondrodysplasia punctata type 2 (RCDP2; 222765)

On personal observation of MMPSI patients, one Russian boy with clinical and electroencephalographic pattern of mixed form (MMPSI and early myoclonic encephalopathy) had rhizomelic chondrodysplasia punctata type 2 (RCDP2; 222,765) from the group of peroxisomal metabolic diseases [20]. Rhizomelic chondrodysplasia punctata type 2 (RCDP2) is caused by homozygous or compound heterozygous mutation in the DHAPAT gene (GNPAT; 602,744), which encodes acyl-CoA:dihydroxyacetonephosphate acyltransferase, on chromosome 1q42. This peroxisomal disorder is characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, micrognathia, dysplastic external ears, eye abnormalities‑cataract and coloboma, congenital contractures, dwarfism, hypotonia, and severe mental retardation. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective.

Genomes Project or Exome Sequencing Project databases. Seizure onset was at age of 1 month with refractory myoclonic seizures that progressed to different polymorphic seizure types and status epilepticus. He also had microcephaly and severe developmental stagnation. Brain imaging showed serious delayed myelination, and EEG demonstrated background slowing with multifocal interictal discharges and occasional periods of burst suppression. The patient doesn't have classical MMPSI characteristics and survived (last observation at the age of 10) with a decrease of

GLY288SER (608167.0010 KCNT1). Ishii et al. in two unrelated Japanese girls with MMPSI identified a de novo heterozygous c.862G-A transition in the KCNT1 gene, resulting in a gly288-to-ser substitution at a highly conserved residue in the

Kawasaki et al. described three infants with malignant migrating partial seizures with KCNT1 mutations accompanied by massive systemic to pulmonary collateral

Madaan with colleagues from Child Neurology Division, Department of Pediatrics, All India Institutes of Medical Sciences (New Delhi, India), in 2018 identified a child with MMPSI who had a novel heterozygous missense mutation in exon 10 of the KCNT1 gene (chr9:138650308; c.808C > C/G (p.Q270E)). Neither quinidine nor ketogenic diet could control his seizures, and the child succumbed to his illness

My personal observation consists of two Russian girls with MMPSI having KCNT1 mutations: one with gly288ser (608167.0010 KCNT1) and the other with

(chr9:138656907C > T, rs752514808). So, it seems that KCNT1 is a major disease-

It is interesting that mutations in KCNT1 also determine another form of epilepsy – nocturnal frontal lobe epilepsy type 5. But the mutation is different from

Milh et al. [18] identified compound heterozygosity for two mutations in exon 2

613577.0005, and 468C-A transversion, resulting in a cys156-to-ter, 613577.0006) in two sisters with malignant migrating partial seizures of infancy. These girls early developed clonic seizures in the second month of life and subsequently demonstrated prolonged, almost continuous migrating seizures of different types with severe neurologic deterioration and lack of psychomotor development [18].

OMIM genetic classification for this type of MMPSI – early infantile epileptic encephalopathy type 16 (615338). The screening of TBC1D24 in an additional set of eight MMPSI patients observed by Milh and colleagues was negative. The TBC1D24 gene encodes a member of the Tre2-Bub2-Cdc16 (TBC) domain-containing RABspecific GTPase-activating proteins, which coordinates peripheral membrane Rab proteins and other GTPases for the proper transport of intracellular vesicles. Coimmunoprecipitation studies showed that the phe229ser mutation impaired the interaction of TBC1D24 with adenosine diphosphate (ADP)-ribosylation factor 6 (ARF6, 600,464), and overexpression of the mutant protein in primary cortical neurons abolished the ability of TBC1D24 to increase neurite length and arboriza-

the cases of MMPSI and is marked .0005–.0008 (ARG928CYS, TYR796HIS,

2.1.5 Early infantile epileptic encephalopathy type 16 (EIEE14; 615338)

of the TBC1D24 gene (686 T-C transition, resulting in a phe229-to-ser,

previously not described mutations c.1066C > T (arg356trp) in exome 12

pharmacoresistant seizures at the age of 7 [14].

Epilepsy - Advances in Diagnosis and Therapy

associated gene for the MMPSI phenotype.

tion, consistent with a loss of function [18].

112

ARG398GLN, and MET896ILE).

arteries with life-threatening hemoptysis and heart failure [16].

pore region of the channel [15].

at 9 months of age [17].
