Mitochondrial myopathy-cerebellar ataxia-pigmentary retinopathy syndrome (ORPHA:502423)
A rare mitochondrial myopathy characterized by motor developmental delay (in infancy), growth impairment and mostly proximal muscle weakness caused by a muscular dystrophy. Muscle biopsy presents myopathic abnormalities and decreased mtDNA content. Electromyography (EMG) shows a myopathic process and serum creatine kinase is increased. The disease is also characterized by early onset non-progressive cerebellar atrophy (particularly cerebellar vermis and hemispheres), corticospinal tract dysfunction, and global or partial cerebral atrophy on brain MRI. Additionally, some patients presented with cognitive deficiencies, skeletal abnormalities, tremors, and retinopathy.
Epidemiology
Approximately 30 cases have been reported worldwide.
Clinical description
Onset generally occurs in newborns, children or adolescents. First symptoms are often observed during the postnatal period: ataxia (secondary to cerebellar atrophy) and proximal muscle weakness. The condition of patients progressively deteriorates during childhood with delayed motor (delayed walking between 2 and 8 years old) and cognitive development. Although cognitive capacities might be normal, most of the children present learning difficulties and intellectual disabilities. In early adolescence, patients show decreased height and weight compared to the average, with an inability to perform complex motor movements. Other symptoms include dysmetria, tremor, dysarthria, adiadochokinesia, and skeletal abnormalities. Pigmentary retinopathy is rarely reported. In patients carrying a dominant mutation, these clinical signs appear later (late adolescence or adulthood).
Etiology
The disease is caused by biallelic mutations in the MSTO1 gene located on chromosome 1q22 with autosomal recessive inheritance. Only one family was described with an apparently autosomal dominant inheritance (mutation c.22 G > A p.Val8Met). MSTO1 encodes for a mitochondrial fusion protein, localized in the cytoplasm and on the outer membrane of the mitochondria. The mutation inactivates the protein leading to a fragmented mitochondrial network.
Diagnostic methods
Diagnosis relies primarily on clinical presentation of cerebellar ataxia and mitochondrial myopathy. MRI shows hypotrophy or damage to the cerebellum. Electromyography confirms the muscular involvement. Muscle biopsies show marked variation in fiber size, with severe atrophy of type I fibers and decreased mtDNA content. Levels of the biomarker creatine kinase, fibroblast growth factor 21 or growth/differentiation factor-15 are increased. Despite the mitochondrial origin, diagnostic criteria based on oxygen consumption or respiratory chain complex activities are not informative for these patients. Cognitive capacities tests support the diagnosis. Sequencing of the MSTO1 gene confirms diagnosis.
Differential diagnosis
Differential diagnoses include Marinesco-Sjögren syndrome, alpha-dystroglycanopathies, Kearns-Sayre syndrome, mitochondrial myopathies, neurogenic muscle weakness-ataxia-retinitis pigmentosa (NARP) syndrome, some hereditary spastic paraplegia (AP5Z1 gene mutations), Leigh syndrome, PMM2-congenital glycosylation disorder, and Pelizaeus-Merzbacher-like 1 disease.
Antenatal diagnosis
Prenatal diagnosis is possible when MSTO1 variants have been previously identified in the family.
Genetic counseling
Transmission is autosomal recessive. Genetic counseling should be offered to at-risk couples informing them of the 25% risk of having an affected child at each pregnancy. In a very few cases, the pattern of inheritance is autosomal dominant. Genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy.
Management and treatment
No curative treatments have been identified. Physiotherapy remains the best long-term management for patients.
Prognosis
Cerebellar atrophy progresses during childhood and stabilizes in early adolescence. After adolescence, the condition appears to stabilize. Above 50 years of age, prognostic data is limited.

                            Last update: 
                            December 2021


                            - Expert reviewer(s): 
                            Pr Alessandra FERLINI  - Dr Marcella NERI