In this study, we report a novel biallelic MICU1 variant, c.385C>T; p.(R129*) in an Iranian patient. Additionally, we review the literature to collect all disease-causing variants and summarize the phenotypes of all reported affected individuals. In this case, we found 44 recorded MPXPS patients in the literature including 39 patients carrying homozygous and 5 patients carrying compound heterozygous variants. Most of the homozygous patients were born to consanguineous parents. Most of the patients were from the Middle East where consanguineous marriage is ranging from 20 to 70% [23]. Up to now, 13 pathogenic MICU1 variants have been reported in previous studies presented with the vast spectrum of symptoms even among patients carrying same pathogenic variants (Supplementary Table 1).
First, MICU1 pathogenic variants including a homozygous splice acceptor site mutation, c.1078–1G>C, and a homozygous splice donor site, c.741+1G>A, were reported in 11 UK-Pakistani and 4 Dutch patients respectively by Logan et al. [1]. All eleven UK-Pakistani patients who carried c.1078-1G>C variant presented with developmental delay. From patients who underwent testing, all presented with elevated CK. In details, 5 patients suffered from microcephaly, 4 patients had proximal weakness, 8 patients showed extrapyramidal signs, 10 patients had learning disability, 6 patients showed speech delay, 4 patients showed skin involvement, and 3 patients had ambulation difficulties. Other features including short stature, ophthalmologic findings, and abnormal gait was observed in some cases. Muscle biopsies were available for 6 of these patients, which all exhibited myopathic features, with diffuse variation in fiber size, increased internal and central nuclei, and clustering of regenerating fibers. Necrotic fibers were rare, except in one subject. Brain MRI was available for 6 patients, out of them 1 patient had signal changes in globus pallidus, and 1 patient showed small cerebellum and 4 were normal. Four patients had skin abnormalities. All four Dutch subjects with c.741+1G>A variant presented with learning disability, ambulation difficulties, and elevated CK. Among these patients, 1 patient had short stature, 2 patients suffered from muscle weakness, 3 patients showed ophthalmologic findings, 3 patients showed extrapyramidal signs, 2 patients had abnormal gait, 2 patients showed developmental delay, 1 patient had speech delay and 2 patients exhibited skin abnormalities. Brain MRI was available for 2 patients; out of them, one patient showed linear calcification in frontal lobe and the other was normal [1].
A homozygous deletion of exon 1 of MICU1 within a 2755-base pair deletion has been reported in 2 cousins by Lewis-Smith et al. [24]. They described a 9-year-old girl with 4 years of episodic fatigue and lethargy. She had short stature and poor growth. No neurologic and ophthalmologic signs were observed. Her cousin, a 12-year-old boy, presented with a positive Gower maneuver due to global muscle weakness, learning difficulties, developmental delay, mild hypotonia, facial dysmorphisms, long thin fingers, bilateral optic atrophy, cataracts, and pendular nystagmus. Rare atrophic fibers and increased internal nuclei showed in muscle biopsy. Echocardiography and MRI were normal. They both showed a normal blood LDH level [24].
The most common variant c.533C>T; p.(Gln185*) has been reported in 21 Middle Eastern Arab patients including 19 patients in homozygous state and 2 compound heterozygous patients concomitant with partial gene duplications. Seventeen out of 20 and 16 out of 19 cases showed elevated CK levels and liver transaminases respectively, 16 out of 20 patients presented with developmental delay, 13 out of 18 patients suffered from learning disability, 4 out of 10 had poor growth, 7 out of 16 subjects had short stature, 10 out of 19 patients showed muscle weakness, 7 out of 20 patients presented with Extrapyramidal signs, 4 out of 11 patients suffered from abnormal gait, 7 out of 11 patients characterized by ambulation difficulties, 5 out of 19 patients showed facial dysmorphisms, 10 out of 10 patients had speech delay, and 4 out of 9 patients had history of frequent falls. Lactate levels of all 10 patients tested were normal. None of 13 patients investigated for skin involvement had skin findings. Other features including seizures, calf muscle hypertrophy, ventricular septal defect (VSD), and liver involvement was observed in some cases [25,26,27].
A missense variant, c.386G>C; p.(R129P), was reported in two patients in compound heterozygous state accompanying by c.1A>G and c.161+1G>A variants in two studies [28, 29]. Wilton et al. [29] reported a 12-year-old female who characterized with myopathy, ataxia, abnormal gait, extrapyramidal signs, ambulation difficulties, developmental delay, learning difficulties, speech delay, generalized seizures, and multiple congenital brain malformations on MRI. She exhibited facial dysmorphisms and ophthalmologic findings. Laboratory tests indicated elevated CK levels, normal serum lactate, and normal liver transaminases [29]. O’Grady et al. [28] reported an 8-year-old boy presented with elevated CK, proximal weakness, extrapyramidal signs, learning difficulties, developmental delay, and abnormal brain MRI. Type 1 fiber predominance was diagnosed in his muscle biopsy [28].
Roos et al. [30] described a 3-year-old girl carrying a homozygous nonsense MICU1 mutation c.553C>T; p.(Arg185*) presented with developmental delay, gait ataxia, clinodactyly, absent proprioceptive reflex, and increased CK. Muscle biopsy showed slow and fast muscle fibers affected by profound atrophy in addition to other signs of a neurogenic muscle atrophy [30]. Chérot et al. identified a compound heterozygous variant in a 4-year-old boy; c.40del; p.(Ala14Leufs*20) & c.1048C>T; p.(Gln350*), presented with intellectual disability, extrapyramidal signs, muscle weakness, dystonia, myoclonus, sensitive-motor axonal neuropathy, hypotonia, and intestinal malrotation [31].
Until now, one MICU1 pathogenic variant, c.1295delA, has been reported [32] in Iran, a Middle East country with consanguinity rates of 38.6% of all marriages [33]. Mojbafan et al. [32] detected two affected sisters who were born to consanguineous parents. The proband was a 5-year-old girl presented with raised CK, poor weight gain, speech delay, and calf hypertrophy. She was ambulant at the age of 5 without positive Gower’s sign. Muscle biopsy showed mild myopathic atrophy with few dispersed or small groups of degenerative/regenerative fibers. Heart echocardiography revealed a mild right side enlargement and mild pericardial infusion. Electromyography and nerve condition velocity (EMG/NCV) study showed myopathic changes. She showed some extrapyramidal signs at the age of 10. Her affected sister was 2 years old who presented with speech delay and raised levels of CK, and liver transaminases. She was normal in her physical examination. EMG/NCV tests showed normal results [32].
Here, we reported the second variant, c.385C>T; p.(R129*), in a 44-year-old Iranian man with elevated hepatic transaminases, elevated CK, raised LDH, learning disability, developmental delay, easy fatigability, muscle weakness, reduced tendon reflexes, ataxia, extrapyramidal signs, gait disturbance, and strabismus. Muscle biopsy showed predominance of type 1 fibers and myopathic atrophy. Multiple necrotic/regenerative fibers, myophagocytosis and severe endomysial fibrosis, and sarcolemma were observed. EMG/NCV study revealed myopathic changes. He had 2 other similarly affected brothers who died at the age of 46 and 48 years, respectively. His extrapyramidal signs and progressive muscular symptoms first presented in his 10s and in his mid-20s he was completely non-ambulant and lost the ability to walk. These manifestations looked to be slowly progressive in line with previous studies [1, 27]. Extrapyramidal signs were observed in 5 subjects of Musa et al. study, one patient at the age of 4 years, three brothers at the mid-20s, and one patient at the age of 10 years [27]. The reported case by Mojbafan et al. also exhibited some extrapyramidal signs at the age of 10 [32]. In accordance with Musa et al. study, our patient had no skin abnormalities [27]. He also had normal height. He had no microcephaly, poor growth, and clinically observed seizures. Most of the patients who underwent testing showed normal LDH, although our case had high level of lactate in accordance with Mojbafan et al. [24, 27, 29, 32]
As mutated residue 129 had been previously reported in two cases and in our case demonstrating that R129 is a hotspot in the MICU1 gene. The nonsense variant found in this study creates a premature protein without EF-hand motifs, which has an important role in transferring Ca2+ through mitochondrial membrane, and leads to a complete loss of function of MICU1 protein.
