Herein, we report a family from southern Sweden with an α-synuclein A53T mutation. The clinical characteristics in the two affected individuals included an early disease manifestation before age 41 and 30 years, rapid progression to a severe phenotype with tremor, rigidity, bradykinesia and gait disturbance, and an initially good response to levodopa treatment. Language and speech difficulties occurred relatively early in the course of the disease, and were followed by cognitive decline. Myoclonic jerks were documented in both individuals.
The proband (III:1) and an unaffected relative (II:3) share identical haplotypes except for the presence of the c.209A mutation in the proband. Although theoretically possible, we consider it highly improbable that I:1 or I:2 would have carried the A53T mutation but remained asymptomatic until their death at age 85 and 93 years. It is impossible to confirm whether II:4 carried the mutation as DNA was not available; however, the parkinsonian symptoms of both II:4 and III:1 were highly similar and have not been reported in any other family member. We conclude that the mutation occurred de novo between generation I and II. We consider these findings the strongest evidence so far that this mutation is sufficient by itself to cause disease.
Cognitive impairment like that seen in the affected members of this family has been reported previously in α-synuclein A53T-associated PD [5
]. However, the severity of cognitive dysfunction was highly variable, occurring early [28
] or late [5
] during the disease course, and several A53T patients remained cognitively intact [12
]. Language and speech impairment has also been found in other A53T patients [6
]. Previous reports also identified prominent myoclonus [6
], severe orthostatic hypotension [15
], and neurogenic bladder disturbance [15
]. These also occurred in this family, and interestingly, in disease associated with SNCA multiplication [21
]. The age at symptom onset was highly variable in published reports, spanning the interval from 20 to 85 years [7
], with means of 45.6 [7
] and 47.9 years [27
]. Thus, the two patients reported here have an early onset of symptoms.
Since both the proband and her father developed dementia, we analyzed genes implicated in hereditary dementia. We found a novel mutation c.488G>A (p.Arg163His; R163H) in the presenilin-2 (PSEN2) gene. This mutation was absent in 170 individuals from the same geographical area (southern Scandinavia) who had been examined genetically for suspected hereditary dementia. Thus, the mutation is rare and not commonly associated with hereditary dementia in this population. A modifying effect of the presenilin-2 R163H mutation in individuals with α-synuclein A53T mutation cannot be excluded with certainty. However, the presenilin-2 R163H mutation was also present in the proband's unaffected mother. We thus suggest that this mutation is a non-pathogenic variant without clinical significance. As DNA was only available from one affected person, no other genetic factors were analysed. A study of members of different families with the α-synuclein A53T mutation could help elucidate whether other genetic factors contribute to phenotypic variability in A53T-related PD.
Our present understanding of the pathogenic effects of the α-synuclein A53T mutation has come from clinical descriptions, genetic analyses, and neuropathological examinations. Here, we present longitudinal clinical and biomarker data from individuals II:4 and III:1, obtained over the course of 10 and 5 years, respectively. II:4 was examined repeatedly at our institution in the 1960s and -70s, III:1 during the years prior to this publication. In both patients, the background rhythm was reduced in EEGs performed 2 (II:4) and 4 years (III:3) after the onset of symptoms. A previous report of EEG results from one patient with A53T mutation showed bitemporal slowing with hyperventilation but a normal background rhythm [6
]. Repeated brain MRI studies were normal in the proband. Previous reports indicate that cranial CT [6
] or MRI [13
] are normal in A53T patients, and one report of mild cerebral atrophy was ascribed to old age [17
]. Both III:1 and II:4 exhibited elevated CSF-protein or albumin concentrations, with repeated measurements showing two-to-four times the mean reference value. CSF monocytes were elevated in all CSF samples analyzed from II:4, but not III:1. In III:1's second lumbar puncture (performed 17 months after the first), the concentration of CSF light-chain neurofilament protein (NFL), a structural axonal protein, was elevated, while the concentration of beta-amyloid(1-42) was considerably lower, possibly reflecting the evolution of the underlying pathological process. CSF-NFL is considered to aid in differentiating PD, where it is normal, from multiple system atrophy (MSA), where it is elevated. Our results suggest that NFL elevation may simply reflect the extent and rate of neurodegeneration. An 123
I-FP-CIT SPECT analysis in III:1 identified clearly reduced dopamine reuptake capacity and cortical blood flow (). Blood flow reduction was most marked in the dominant hemisphere, consistent with the observed language deficits. These results suggest that there is an underlying diffuse encephalopathic and/or neurodegenerative process in α-synuclein A53T-associated disease which affects the cerebral cortex and dopaminergic system, with increased vascular wall permeability causing protein leakage into the CSF, cell death, decreased cortical blood flow, dopamine depletion and slowed EEG background rhythm. These findings are consistent with the abundant cortical α-synuclein deposition found in post mortem
examinations of the brains of α-synuclein A53T-positive individuals [15
This study is limited by the low number (two) of affected individuals. There may be alternative explanations for the increase in CSF cell count and protein or albumin levels, such as a gliotic reaction to the neurosurgical treatment in II:4, a low-level asymptomatic infectious disease, or another unknown cause. Repeated lumbar puncture by itself is known to cause slight elevation of CSF-protein and cell count, although this does not explain why both values were raised in the very first examination in both individuals. Additional clinical data from other A53T individuals will reveal whether these conclusions can be applied generally.