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CASE REPORT
Year : 2023 | Volume
: 26
| Issue : 1 | Page : 73-75
Mitochondrial calcium uptake 1 (MICU1) gene-related myopathy with extrapyramidal signs: A clinico-radiological case report from India
Debaleena Mukherjee, Adreesh Mukherjee, Subhadeep Gupta, Souvik Dubey, Alak Pandit
Department of Neurology, Bangur Institute of Neurosciences, Institute of Post Graduate Medical Education and Research, Kolkata, West Bengal, India
Correspondence Address:
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/aian.aian_904_22
Abstract
Myopathy with extrapyramidal signs (MPXPS) is a rarely reported entity worldwide, manifesting as a muscular dystrophy with movement disorders. It results from mutations in the mitochondrial calcium uptake 1 (MICU1) gene. We hereby describe a 17-year-old boy who presented with proximal myopathy, calf muscle hypertrophy, and skeletal deformities along with choreiform movements of his upper extremities. Muscle MRI revealed a distinctively early involvement of adductors with sparing of antero-lateral compartment of thigh. This report expands the clinico-radiological presentation and to the best of our knowledge, is the first report of MICU-related MPXPS from India.
Keywords: Dystrophinopathy, LGMD, MICU, mitochondrial disease, MPXPS, muscle metabolism, muscular dystrophy
Introduction 
Myopathy with extrapyramidal signs (MPXPS) is a rare autosomal recessive entity characterized by an intriguing combination of muscle disease and movement disorders, resulting from mutations in the mitochondrial calcium uptake 1 (MICU1) gene.[1] Reported sparsely in some populations outside India, we hereby present this case which, to the best of our knowledge, is the first report of MICU-related MPXPS from India. It expands the phenotypic presentation and explores the radiological features in muscle magnetic resonance imaging (MRI) which can be instrumental in differentiating from other commonly encountered myopathies including dystrophinopathies and limb girdle muscular dystrophies (LGMD).
Case History This 17-year-old male patient born out of non-consanguineous parentage with normal birth and developmental history presented with progressive proximal predominant weakness of all four limbs since 10 years of age. He further developed abnormal posturing of both upper limbs and slurring of speech for last six years. He had poor scholastic performance. There was no similar history in the family.
General examination revealed high arched palate with a normal arm span/height ratio. Neuromuscular examination showed differential hypertrophy and atrophy of muscles around the hip and shoulder girdle with bilateral scapular winging. In the lower limbs, wasting of the adductor compartment with sparing of quadriceps and bilateral calf muscle hypertrophy were noted. Additionally, overriding of the 4th toe on the 5th and pes cavus were observed [Figure 1]. He had symmetric proximal predominant weakness with absent deep tendon reflexes. The speech was dysarthric. Extrapyramidal features in the form of dystonia and choreiform movements of the upper extremities were noted [Video 1] [Additional file 1] . Investigations showed elevated CPK (creatine phosphokinase, 2240 U/L). Metabolic parameters including thyroid profile, glycemic parameters, calcium, phosphorous, and vitamin D levels were normal. Electromyography confirmed myopathic pattern. Muscle MRI showed fatty infiltration in bilateral gluteus minimus, adductor magnus and brevis, obturators, and pectineus with distinct sparing of the anterolateral compartment, which also correlated clinically [Figure 2]. Leg muscles were normal radiologically, further reflecting early proximal predilection of this disease.
Figure 1: Clinical features showing (a) bilateral scapular winging, (b) and (c) pes cavus, (d) overriding of the 4th toe on the 5th, (e) bilateral atrophy of the medial adductor compartment with sparing of the quadriceps, (f) bilateral calf muscle hypertrophy
Figure 2: Magnetic resonance imaging of muscles of pelvis and thigh showing (a) T1-weighted coronal image showing fatty infiltration of bilateral adductors (adductor brevis and magnus), (b) T1-weighted axial image of pelvis showing bilateral fatty infiltration of gluteus minimus with sparing of gluteus maximus and medius, (c) T1-weighted axial image of pelvis showing bilateral fatty infiltration of pectineus and adductors, (d) and (e) T1-weighted axial image of thigh muscles showing fatty infiltration of bilateral adductor brevis and magnus with sparing of adductor longus and quadricepsGenetic study revealed a homozygous 3′ splice site variation in intron 9 of the MICU1 gene (chr10:g. 74167796C > G; Depth: 39x) that affects the invariant AG acceptor splice site of exon 10 (c.1072-1G > C; ENST00000361114.5). The observed variation has previously been reported, in a homozygous state, in patients affected with myopathy[1] and is reported as pathogenic in the ClinVar database.[2]
He received physical therapy and trihexyphenidyl. He has been routinely followed up for three years. While the extrapyramidal features have remained relatively stable, he has developed progressive wasting of muscles without significant deterioration in weakness [Video 2] [Additional file 2] .
Discussion MPXPS is an autosomal recessive disorder resulting from a homozygous mutation in MICU1 gene, located on chromosome 10q22.[3] With only a few cases reported around the world in Iranian, Middle eastern, Dutch, and UK-Pakistani families, it has a prevalence of <1/1000000.[1],[4],[5],[6],[7] Skeletal muscle calcium regulation and homeostasis plays a key role in excitation–contraction coupling, relaxation, sarcolemmal repair, and exercise adaptation. This is influenced by the delivery of Ca2+ to the mitochondrial matrix via the mitochondrial Ca2+ uniporter (MICU). MICU1 is a key regulator of MICU by sensing calcium levels and functions both as an activator or inhibitor of mitochondrial calcium uptake. Loss-of-function mutation in MICU1 results in neuromuscular disease.[5],[8],[9]
The myopathy presents as childhood onset proximal predominant weakness closely resembling dystrophinopathies and LGMDs. Learning difficulties are common. The appearance of extrapyramidal features such as chorea, athetosis, dystonia, tremor, and orofacial dyskinesias is the key differentiator. As per previous authors, while the muscle weakness appears to have a static course, extrapyramidal symptoms progress. However, we found a reverse trend during follow-up. Other features include delayed speech and motor milestones, hypotonia, optic atrophy, ptosis, ophthalmoplegia, ataxia, peripheral neuropathy, and microcephaly. Such multiaxial involvement underscores the underlying mitochondrial pathology.[1],[7],[10]
The presence of calf muscle hypertrophy as seen in this case has been previously observed even in asymptomatic patients.[5] Calf muscle hypertrophy in the background of proximal muscle weakness raised the suspicion of muscular dystrophies which present similarly including dystrophinopathies and LGMD (including sarcoglycanopathy, fukutin-related myopathies, and early stages of dysferlinopathies prior to the onset of calf atrophy). Among proximal muscles, the sparing of quadriceps amid severe involvement of adductors was noteworthy. The radiological pattern of involvement of adductors (brevis and magnus) and only gluteus minimus among gluteals with sparing of quadriceps, hamstrings, and all leg muscles differentiated from other muscular dystrophies such as dystrophinopathy and LGMD. Moreover, the presence of extrapyramidal features was a crucial clue. Additional phenotypic markers included the presence of scapular winging, pes cavus, and overriding of the 4th toe on the 5th.
Elevation of liver enzymes was noted similar to previous cases. MRI brain was normal in our patient, although previously multifocal brain malformations including polymicrogyria, dysmorphic basal ganglia, hypoplastic anterior limbs of internal capsules, mild cerebellar dysplasia, and white matter abnormalities have been described.[7],[10]
Conclusion This case highlights the recognition of extrapyramidal features and skeletal deformities as key features in differentiating MICU-related myopathy from other myopathies with proximal predominant weakness and calf muscle hypertrophy. Muscle MRI of pelvis and lower limbs has demonstrated a pattern of fatty infiltration of the adductors with sparing of quadriceps and hamstrings which also correlated clinically. While muscle MRI can be largely instrumental in aiding differentiation from other myopathies, lack of previous data in MICU-related myopathy warrants future studies for consistency.
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This case report was prepared in accordance with the ethical standards and written informed consent was duly taken. We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
What is known? Myopathy with extrapyramidal signs presented with an intriguing combination of muscular dystrophy with movement disorders.
What is new? An expanded clinical spectrum was observed including the presence of pes cavus, overriding of 4th on 5th toe and scapular winging. Radiological aspects have been explored with muscle MRI, demonstrating a typical pattern of involvement of adductors (brevis and magnus) and only gluteus minimus among gluteals with sparing of quadriceps, hamstrings, and all leg muscles differentiating from other muscular dystrophies such as dystrophinopathy and LGMD. While previous authors have opined that muscle weakness appears to have a static course and extrapyramidal symptoms progress, we found a reverse trend during follow-up.
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