The m.9143T>C Variant: Recurrent Infections and Immunodeficiency as an Extension of the Phenotypic Spectrum in MT-ATP6 Mutations?

Abstract

Pathogenic variants in the MT-ATP6 are a well-known cause for maternally inherited mitochondrial disorders associated with a wide range of clinical phenotypes. Here, we present a 31- year old female with insulin-dependent diabetes mellitus, recurrent lactic acidosis and ketoacidosis recurrent infections with suspected immunodeficiency with T cell lymphopenia and hypogammaglobulinemia as well as proximal tetraparesis with severe muscle and limb pain and rapid physical exhaustion. Muscle biopsy and respiratory chain activities were normal. Single-exome sequencing revealed a variant in the MT-ATP6 gene: m.9143T>C. Analysis of further specimen of the index and mother (segregation studies) revealed the highest mutation load in muscle (99% level of mtDNA heteroplasmy) of the index patient. Interestingly, acute metabolic and physical decompensation during recurrent illness was documented to be a common clinical feature in patients with MT-ATP6 variants. However, it was not mentioned as a key symptom. Thus, we suggest that the clinical spectrum might be expanded in ATP6-associated diseases.

Variants in Human ATP Synthase Mitochondrial Genes: Biochemical Dysfunctions, Associated Diseases, and Therapies

“…Other identified MT-ATP6 variants include the m.8858G>A variant in a sporadic case of NARP-MILS [128]; the m.8936T>A in a young boy with atypical mitochondrial Leigh syndrome associated with bilateral basal ganglia calcifications [129]; m.9143T>C in a patient with insulin-dependent diabetes mellitus, recurrent lactic acidosis, infections, and immunodeficiency [130]; m.9154C>T in a patient with neuropathy, cerebellar ataxia, and IgA nephropathy [131]; and m.9171A>G in a patient with mitochondrial retinopathy with atrophy [132]. The three variants m.8572G>A, the m.8578C>T and m.8812A>G were found in patients with adult-onset spinocerebellar ataxia (SCA) [133].…”

“…For example, MT-ATP6-related Leigh disease has been reported in cases with adult onset [149,150] or in patients with MRI findings that differ from classic MILS, presenting delayed myelination, cerebral atrophy/microcephaly, or no pathology [151,152]. In addition, new biochemical dysfunctions and disease symptoms have been added to the canonical phenotypic spectrum related to MT-ATP6 variants, such as carboxylase deficiency [153] or recurrent infections and immunodeficiency [130].…”