Natural History of Polymerase Gamma–Related Ataxia

Abstract

A BS TRACT: Background: Mutations in the mitochondrial DNA polymerase gamma are causing a wide phenotypic spectrum including ataxia as one of the most common presentations. Objective: The objective of this study was to determine the course of disease of polymerase gamma-related ataxia. Methods: In a prospective natural history study, we assessed 24 adult ataxia patients with biallelic polymerase gamma mutations for (1) severity of cerebellar dysfunction using the Scale for the Assessment and Rating of Ataxia score, (2) presence of nonataxia signs using the Inventory of Non-Ataxia Symptoms, (3) gray-and whitematter changes in brain MRI, and (4) findings in nerve conduction studies. Results: Assessment included follow-up visits up to 11.6 years. The Scale for the Assessment and Rating of Ataxia showed a mean annual increase of 1.02 AE 0.78 points/year. Disease progression was faster in patients with age at onset ≤ 30 years (1.5 Scale for the Assessment and Rating of Ataxia points/year) than with later onset (0.5 points/year); P = 0.008. The Inventory of Non-Ataxia Symptoms count increased by 0.30 AE 0.4 points/ year. External ophthalmoplegia, brain stem oculomotor signs, areflexia, and sensory deficits were the most common nonataxic features. On MRI cerebellar atrophy was mild. T2 signal alterations affected mostly cerebellar white matter, middle cerebellar peduncles, thalamus, brain stem, and occipital and frontal white matter. Within 4 years, progression was primarily observed in the context of repeated epileptic seizures. Nerve conduction studies revealed axonal sensory peripheral neuropathy with mild motor nerve involvement. Exploratory sample size calculation implied 38 patients per arm as sufficient to detect a reduction of progression by 50% in hypothetical interventions within a 1-year trial. Conclusion:The results recommend the Scale for the Assessment and Rating of Ataxia as a primary outcome measure for future interventional trials in polymerase gamma-related ataxia.

Capturing clinical progression in multisystemic genetic ataxias: lessons from a prospective study of 884 patients with autosomal recessive or early-onset ataxia

“…Albeit preliminary, given the limited number of observations and heterogeneous time courses, such data are urgently required for trial planning, as treatments are on the horizon for several of these ARCAs -either for the whole ataxia disease type 33 or for individual patients thereof susceptible to individualized genetic treatments 34 . The progression rates of 1.56 SARA points/year in POLG-ataxia and 0.57 SARA points/year in SPG7 corroborate and extend earlier findings in these ataxias 35, 36 . In ARSACS, where responsiveness of the SARA in annual intervals is controversial 14, 37 , our data suggests that even without ceiling effects, the SARA may not be sensitive to change over 1 year.…”

Responsiveness of the Scale for the Assessment and Rating of Ataxia and Natural History in 884 Recessive and Early Onset Ataxia Patients

“…39 The progression rates of 1.56 SARA points/yr in POLG-ataxia and 0.57 SARA points/yr in SPG7 corroborate and extend earlier findings in these ataxias. 40,41 In ARSACS, where responsiveness of the SARA in annual intervals is controversial, 14,42 our data suggest that even without ceiling effects, the SARA may not be sensitive to change over 1 year. Larger natural history studies accounting, for example, for different mutations (c.8844delT SACS founder mutation vs other mutations) are needed to address this question.…”

Sensory ataxic neuropathy with dysarthria and ophthalmoparesis (SANDO) syndrome associated with two heterozygous POLG mutations

“…The phenotypes include myocerebrohepatopathy spectrum disorder (MCHS) and Alpers-Huttenlocher syndrome (AHS), presenting in the neonatal/infantile period and chronic progressive external ophthalmoplegia (CPEO), spinocerebellar ataxia with epilepsy (SCAE), mitochondrial recessive ataxia syndrome(MIRAS), myoclonic epilepsy myopathy sensory ataxia (MEMSA), and sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO), presenting later in life. 1,2 Our patient fulfilled the clinical triad for SANDO. This phenotype was first demonstrated by Fadic et al in 1997, associated with multiple mtDNA deletions.…”

“…Mutations in POLG can cause a wide spectrum of neurological diseases, which are phenotypically heterogenous. 1 Among the various phenotypes, ataxia neuropathy spectrum (ANS) includes mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO).The classical clinical triad of sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) has been reported only in a small subset of patients with POLG mutations. 3 We…”