The natural history of infantile mitochondrial DNA depletion syndrome due to RRM2B deficiency

Abstract

Mitochondrial DNA (mtDNA) depletion syndrome (MDDS) encompasses a group of genetic disorders of mtDNA maintenance. Mutation of RRM2B is an uncommon cause of infantileonset encephalomyopathic MDDS. Here we describe the natural history of this disease. Methods Multinational series of new genetically confirmed cases from six paediatric centres. Results Nine new cases of infantile-onset RRM2B deficiency, and 22 previously published cases comprised a total cohort of 31 patients. Infants presented at a mean of 1.95 months with truncal hypotonia, generalised weakness and faltering growth. Seizures evolved in 39% at a mean of 3.1 months. Non-neurological manifestations included respiratory distress/failure (58%), renal tubulopathy (55%), sensorineural hearing loss (36%), gastrointestinal disturbance (32%), eye abnormalities (13%), and anaemia (13%). Laboratory features included elevated lactate (blood, CSF, urine, MR spectroscopy), ragged-red and cytochrome c oxidase-deficient fibres, lipid myopathy and multiple oxidative phosphorylation enzyme deficiencies in skeletal muscle. Eight new RRM2B variants were identified. Patients with biallelic truncating variants had the worst survival. Overall survival was 29% at 6 months and 16% at 1 year. Conclusion Infantile-onset MDDS due to RRM2B deficiency is a severe disorder with characteristic clinical features and extremely poor prognosis. Presently management is supportive as there is no effective treatment. Novel treatments are urgently needed.

Molecular Genetics Overview of Primary Mitochondrial Myopathies

“…Other less common RRM2B phenotypes have been described as progressive external ophthalmoplegia with bulbar dysfunction, fatigue, and muscle weakness with autosomal dominant transmission in adults or with a recessive trait and childhood-onset [138,150,151].…”

Mitochondrial disease in children

“…The MDDS may be grouped according to clinical presentation (myopathic, encephalomyopathic, hepatocerebral or multisystem disorder) or underlying genetic mechanism (defect of the mtDNA replication apparatus, mtDNA repair, nucleoside metabolism or mitochondrial dynamics) [20,21]. Infantile‐onset MDDS include RRM2B deficiency, which presents shortly after birth with progressive myopathy variably associated with sensorineural hearing loss (SNHL), renal tubulopathy and seizures [22]; Alpers–Huttenlocher syndrome (see below) and deficiencies of DGUOK and MPV17, which cause infantile liver failure with/without encephalopathic features; and TK2 deficiency, which presents as a severe progressive myopathy with elevated lactate and creatine kinase [20].…”

“…Without aminoglycoside exposure, individuals with this variant may have normal hearing until well into adult life, implying a role for newborn screening for the variant followed by lifelong avoidance of aminoglycosides in at‐risk individuals [74]. Childhood‐onset mitochondrial syndromes in which hearing loss is a prominent feature include MERRF, MELAS, KSS and deficiencies of SUCLA2, BCS1L, RRM2B, SERAC1, RMND1 and TRNT1 [19,22,27,38,47,49,75‐78].…”

Reply to: “Mitochondrial Parkinsonism due to SPG7/Paraplegin variants with secondary mtDNA depletion”

“…Mitochondrial DNA depletion syndromes (MDS) are typically tissue‐specific disorders, and epilepsy can feature in severe pediatric cases. Nevertheless, 60% of cases of well‐established MDS did not manifest seizures . Moreover, it would be premature to label Hereditary spastic paraplegia ( SPG7 ‐HSP) an MDS.…”