Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene

Abstract

We present a patient with unusual episodes of muscular weakness due to homozygous deletion of exon 2 in the MICU1 gene. Forty-three patients from 33 families were previously described with homozygous and compound heterozygous, predominantly loss of function (LoF) variants in the MICU1 gene that lead to autosomal recessive myopathy with extrapyramidal signs. Most described patients developed muscle weakness and elevated CK levels, and half of the patients had progressive extrapyramidal signs and learning disabilities. Our patient had a few severe acute episodes of muscle weakness with minimal myopathy features between episodes and a strongly elevated Creatinine Kinase (CK). Whole exome sequencing (WES) was performed and the homozygous deletion of exon 2 was suspected. To validate the diagnosis, we performed an RNA analysis of all family members. To investigate the possible impact of this deletion on the phenotype, we predicted a new Kozak sequence in exon 4 that could lead to the formation of a truncated MICU1 protein that could partly interact with MCU protein in a mitochondrial Ca2+ complex. We suspect that this unusual phenotype of the proband with MICU1-related myopathy could be explained by the presence of the truncated but partly functional protein. This work helps to define the clinical polymorphism of MICU1 deficiency better.

Dolichocephaly, Arachnodactyly, Diplopia, and Distal Myopathy – Novel Phenotype of MICU1 Variant c.553C>T

“…Therefore, the case expands the scope of the phenotypic spectrum and highlights that MICU1 variants manifest with broader phenotypic heterogeneity than previously thought. Previously unreported phenotypic features of the index patient included dolichocephaly, arachnodactyly, broad nasal bridge, distal myopathy, and diplopia [5][6][7][8][9][10][11][12][13][14][15][16]. Even a larger series of MICU1 patients did not report them [9].…”

“…The MICU1 protein functions as a calcium uniporter protein and is responsible for delivering calcium ions to the mitochondrial matrix [5]. Pathogenic variants in MICU1 manifest phenotypically with multisystem disease affecting the skeletal muscles (proximal myopathy, ptosis, ophthalmoparesis, dysarthria, scapula alata), the brain (cognitive impairment, mental retardation, attention deficit, depression, insomnia, seizures, extrapyramidal abnormalities (chorea, dystonia, athetosis, tremor, orofacial dyskinesia, tics), ataxia, nystagmus, dysarthria, polymicrogyria, dysmorphic basal ganglia, hypoplastic anterior limbs of internal capsules, cerebellar dysplasia, optic atrophy), the peripheral nerves (axonal neuropathy), the heart (dilated cardiomyopathy), the skeleton (microcephaly, hypertelorism, high arched palate, pes cavus, clinodactyly, hyperlordosis, hyperkyphosis, radioulnar synostosis, low-set ears), the endocrine organs (short stature, hypothyroidism), and the eyes (cataract) [5][6][7][8][9][10][11][12][13][14][15][16]. The most common phenotype is an autosomal recessive, childhood-onset myopathy with proximal muscle weakness with extrapyramidal signs (MPXPS) (OMIM #615673) [15].…”

Autosomal Recessive Mitochondrial Myopathy due to MICU-1 Variants

“…About 50 patients with MICU-1-related myopathy have been reported to date. [ 6 ] In some of these patients, serum creatine-kinase was excessively high. [ 6 ] Some patients were also presented with seizures, microcephaly, ataxia, hypotonia, ptosis, ophthalmoparesis, and neuropathy.…”

“…[ 6 ] In some of these patients, serum creatine-kinase was excessively high. [ 6 ] Some patients were also presented with seizures, microcephaly, ataxia, hypotonia, ptosis, ophthalmoparesis, and neuropathy. [ 6 ] Has the index patient manifested with any of these additional phenotypic traits?…”

“…[ 6 ] Some patients were also presented with seizures, microcephaly, ataxia, hypotonia, ptosis, ophthalmoparesis, and neuropathy. [ 6 ] Has the index patient manifested with any of these additional phenotypic traits? Have epileptiform discharges been recorded on EEG?…”