A LRSAM1 mutation links Charcot–Marie–Tooth type 2 to Parkinson's disease

Abstract

LRSAM1 mutations have been found in recessive and dominant forms of Charcot–Marie–Tooth disease. Within one generation of the original Dutch family in which the dominant LRSAM1 mutation was identified, three of the five affected family members have developed Parkinson's disease between ages 50 and 65 years, many years after neuropathy onset. We speculate that this late‐onset parkinsonism is part of the LRSAM1 phenotype, thus associating a hitherto peripheral nerve disease with a central nervous system phenotype. How the mutated Lrsam1 protein, which normally has E3 ubiquitin ligase activity and is expressed in the nervous system, impacts on substantia nigra neurons is unclear.

Charcot–Marie–Tooth disease type 2G redefined by a novel mutation in LRSAM1

“…The dominant mutations described so far are associated with a relatively mild, very slowly progressive sensorimotor axonal neuropathy initially affecting lower limbs. 26 Our study broadens the current knowledge regarding the phenotypic and genetic spectrum associated with LRSAM1. 19 Additionally, 3 aged patients carrying a LRSAM1 frameshift mutation developed Parkinson disease, suggesting a potential role for mutated LRSAM1 in the degeneration of substantia nigra.…”

“…19 Additionally, 3 aged patients carrying a LRSAM1 frameshift mutation developed Parkinson disease, suggesting a potential role for mutated LRSAM1 in the degeneration of substantia nigra. 26 Our study broadens the current knowledge regarding the phenotypic and genetic spectrum associated with LRSAM1. Reduced penetrance is generally rarely observed in CMT subtypes, 27 yet it appears to be a common phenomenon in the context of LRSAM1-related neuropathies, as demonstrated by the current and previous investigations.…”

A novel missense mutation of CMT2P alters transcription machinery

“…27 Remarkably, a subgroup of patients with mutations in LRSAM1 have developed phenotypes of Parkinson disease. 28 In summary, we have identified a novel missense mutation that alters cysteine to arginine in the RING domain of LRSAM1. We have shown multiple lines of evidence suggesting that this mutation is causal for CMT2P.…”

A new alpha-synuclein missense variant (Thr72Met) in two Turkish families with Parkinson's disease

“…LRSAM1 disruptive variants are an established cause of autosomal dominant axonal sensorimotor neuropathy [25]. Of note, in a previously published pedigree with HMSN2, three out of five affected members developed PD in addition to neuropathy [26], suggesting a possible link between LRSAM1 defects and the development of PD. In family 2, however, the LRSAM1 variant did not segregate with PD, as one of the two clinically affected parkinsonian cases (the index case, III-1) did not carry this variant.…”