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

Pathogenic variants in mitochondrial calcium uptake 1 (MICU1) manifest phenotypically heterogeneously but most frequently in the brain and skeletal muscle. Dolichocephaly, arachnodactyly, diplopia, and distal myopathy have not been reported in carriers of a pathogenic MICU1 variant. The patient is a 23-year-old female with consanguineous parents (first cousins) who was a carrier of the homozygous MICU1 variant c.553C>T, phenotypically presenting with developmental delay, intellectual disability, ataxia, dysmorphia (dolichocephaly, arachnodactyly, clinodactyly, hypertelorism, wide nasal bridge), myopathy (ptosis, double vision, strabismus, distal limb weakness, diffuse wasting, hypotonia), hyperextensible joints and hyperkyphosis. Features not previously described were dolichocephaly, arachnodactyly, broad nasal bridge, double vision, and distal myopathy. She was treated with physical therapy, speech therapy, and occupational therapy and received escitalopram and mirtazapine for concomitant depression, anxiety disorder, and insomnia. The presented case shows that the phenotypic heterogeneity of pathogenic MICU1 variants is even greater than previously assumed. Treatment of MICU1-related phenotypes is symptomatic, but these patients benefit from physical therapy, behavioral therapy, speech therapy, and antidepressant treatment.


Case Presentation
The patient is a 23-year-old female, height 165 cm, weight 36 kg, who was diagnosed with mitochondrial myopathy due to the homozygous variant c.553C>T in exon 6 of the MICU1 gene.The patient presented with developmental delay at the age of three and cognitive impairment that manifested first in elementary school (Table 1).For this reason, she moved to a special school, which she attended for the next 12 years with below-average academic performance.At the age of 12, she developed gait disturbance due to weakness in the right lower extremities.Her medical history was also positive for recurrent abdominal pain, but clinical examination, blood tests, and abdominal ultrasound were repeatedly normal.Family history revealed no evidence of cerebral, muscle, or cardiac disease, but her parents were first-degree cousins.The parents, brother, and two sisters were phenotypically unaffected.A second neurological examination was performed at the age of 23 years because the patient reported recurrent diplopia when looking in all directions but without diurnal fluctuations for three years.She presented as a depressed, anxious, taciturn woman who followed instructions correctly but inconsistently.

Phenotype
Her face was mildly dysmorphic with dolichocephalus, hypertelorism, strabismus, and mild ptosis bilaterally (Figure 1).She was near-sighted and had significant muscle soreness in her neck.There was no ophthalmoparesis.In the upper limbs, there was distal muscle weakness of the hand and finger muscle (M5-), diffuse wasting, arachnodactyly, clinodactyly (Figure 2), hypotonia, hyperextensible finger and wrist joints, decreased tendon reflexes, and a positive snap reflex on the left side.In the lower limbs, there was discrete dorsiflexion weakness bilaterally, reduced tendon reflexes, and diffuse muscle wasting, but without fasciculations, pseudohypertrophy, or sensory disturbances.She had mild ataxia and had difficulty performing the Unterberger treadmill test correctly and staying on line while walking with her eyes open.It was impossible to walk on the line with her eyes closed.She did not have cachexia.Blood tests revealed erythrocytosis, neutrophilia, lymphopenia, hyperbilirubinemia, mildly elevated transaminases, and mild elevation of creatine-kinase.Tests for vasculitis were normal.Needle electromyography, nerve conduction studies, and repetitive nerve stimulation were normal.Antibodies against acetylcholine receptors and MUSK were negative.MRI of the orbita was normal.Abdominal ultrasound was normal.She benefited from regular physical therapy, speech therapy, and behavioral therapy.
The causative mutation in the index patient has only been described once [6].The previously reported patient carrying the c.553C>T variant was a 5-year-old female born as the first child of consanguineous Turkish parents.Initially, she suffered from delayed motor milestones, delayed speech development, moderate ataxia with frequent falls, motor restlessness, exercise intolerance, decreased attention, and insomnia with frequent awakenings.At 5 years of age, cognitive impairment, muscle weakness, hypotonia, hyperlordosis, and clinodactyly also occurred [6].The cerebral MRI was normal.Compared to the index patient, this patient showed similar features.

Conclusions
The presented case shows that the phenotypic heterogeneity of pathogenic MICU1 variants is even greater than previously assumed.In addition to previously reported phenotypic features, carriers of the c.553C>T variant may exhibit dolichocephaly, arachnodactyly, broad nasal bridge, distal myopathy, and diplopia.Treatment of MICU1-related phenotypes is symptomatic, but these patients benefit from physical therapy, occupational therapy, speech therapy, and antidepressant treatment.
info: All authors have declared that no financial support was received from any organization for the submitted work.Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work.Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.

TABLE 1 : Patients carrying pathogenic MICU1 variants reported until the end of 2023
Clinical neurological examination at the age of 14 years revealed startleness but no hyperekplexia, social withdrawal, avoidance of eye contact, general wasting, and hyperkyphosis of the thoracic spine.Blood tests revealed recurrent mild elevation of creatine-kinase.Needle electromyography was normal in muscles with and without weakness.Nerve conduction studies were normal.A muscle biopsy from the left biceps muscle revealed only nonspecific changes.The cerebral CT was normal.The EEG only showed increased background slowing (diffuse, intermittent theta waves without drowsiness).Neuropsychological testing revealed adjustment disorders, anxiety, depression, moderate intellectual disability, a negative self-image, and feelings of being unloved.Genetic testing revealed the homozygous variant c.553C>T in exon 6 of the MICU1 gene.