Aymé-Gripp syndrome (AGS) is an autosomal dominant multisystem disorder caused by specific heterozygous variants in MAF. The resulting aberrant protein shows impaired GSK-mediated MAF phosphorylation. AGS is characterized by congenital cataracts, sensorineural hearing loss, short stature, intellectual disability, and distinctive facial features with brachycephaly. Cardiac and joint phenotypes are present in nearly half of patients. We review information on 10 published individuals with MAF mutations and clinical AGS and describe five additional patients, including three with novel mutations. Joint problems, typically including radioulnar synostosis and joint limitations, were present in 9/15 patients. Hip replacement in young adulthood was needed in four patients. Pericarditis occurred in 6/15 individuals. An automated facial analysis of 2D photos was used to compare the facial phenotype of 13 individuals from the literature or reported here, with facial photos of a control cohort of unaffected individuals and a cohort of Down syndrome patients. A multiclass approach yielded an accuracy of 86.86% and 89.05%, respectively, in two independent experiments compared to a random chance of 37.74%. In binary comparisons of AGS and Down syndrome, the area under the curve (AUC) was 0.994 (P < .001) and 1.0 (P < .001), respectively. Binary comparisons of AGS and unaffected controls yielded AUC of 0.994 (P < .001) and 0.989 (P = .003), respectively, suggesting that the facial phenotype of AGS could clearly be distinguished from unaffected individuals and from Down syndrome patients. Automated facial analysis may be helpful in the identification and evaluation of individuals suspected to have AGS.

MSTO1 encodes a cytosolic mitochondrial fusion protein, misato homolog 1 or MSTO1. While the full genotype–phenotype spectrum remains to be explored, pathogenic variants in MSTO1 have recently been reported in a small number of patients presenting with a phenotype of cerebellar ataxia, congenital muscle involvement with histologic findings ranging from myopathic to dystrophic and pigmentary retinopathy. The proposed underlying pathogenic mechanism of MSTO1-related disease is suggestive of impaired mitochondrial fusion secondary to a loss of function of MSTO1. Disorders of mitochondrial fusion and fission have been shown to also lead to mitochondrial DNA (mtDNA) depletion, linking them to the mtDNA depletion syndromes, a clinically and genetically diverse class of mitochondrial diseases characterized by a reduction of cellular mtDNA content. However, the consequences of pathogenic variants in MSTO1 on mtDNA maintenance remain poorly understood. We present extensive phenotypic and genetic data from 12 independent families, including 15 new patients harbouring a broad array of bi-allelic MSTO1 pathogenic variants, and we provide functional characterization from seven MSTO1-related disease patient fibroblasts. Bi-allelic loss-of-function variants in MSTO1 manifest clinically with a remarkably consistent phenotype of childhood-onset muscular dystrophy, corticospinal tract dysfunction and early-onset non-progressive cerebellar atrophy. MSTO1 protein was not detectable in the cultured fibroblasts of all seven patients evaluated, suggesting that pathogenic variants result in a loss of protein expression and/or affect protein stability. Consistent with impaired mitochondrial fusion, mitochondrial networks in fibroblasts were found to be fragmented. Furthermore, all fibroblasts were found to have depletion of mtDNA ranging from 30 to 70% along with alterations to mtDNA nucleoids. Our data corroborate the role of MSTO1 as a mitochondrial fusion protein and highlight a previously unrecognized link to mtDNA regulation. As impaired mitochondrial fusion is a recognized cause of mtDNA depletion syndromes, this novel link to mtDNA depletion in patient fibroblasts suggests that MSTO1-deficiency should also be considered a mtDNA depletion syndrome. Thus, we provide mechanistic insight into the disease pathogenesis associated with MSTO1 mutations and further define the clinical spectrum and the natural history of MSTO1-related disease.Electronic supplementary materialThe online version of this article (10.1007/s00401-019-02059-z) contains supplementary material, which is available to authorized users.