Novel compound heterozygous synaptojanin‐1 mutation causes l‐dopa‐responsive dystonia‐parkinsonism syndrome

Abstract

but preserved repetition and naming. Comprehension was impaired. She was unable to read or write. Verbal memory and visuospatial processing were intact. She exhibited symmetric parkinsonism characterized by rigidity, bradykinesia, resting tremor, and impaired postural reflexes (Supporting Information Video is available online). Brain MRI showed asymmetric frontal atrophy ( Fig. 1A). She reached a state of akinetic mutism at age 69 and died at age 70.Plasma progranulin levels were 27 ng/ml (normal threshold < 61 ng/ml). 1 GRN sequencing showed a novel heterozygous deletion (g.1642_1645delTGAG) in the 3' flanking region of exon 7 (IVS7 1 1delTGAG), a highly conserved region in vertebrates ( Supplementary Figure). In silico analysis predicted that the wild-type sequence is localized in a donor splice site, which is abolished by the deletion. Microtubule Associated Protein Tau (MAPT) and Chromosome 9 Open Reading Frame 72 (C9ORF72) were negative.At autopsy, the fresh brain weighed 900 grams. Macroscopically, there was severe atrophy of the frontal and temporal lobes. Histologically, there was severe neuronal loss and gliosis involving the neocortex, caudate nucleus, putamen, globus pallidus, hippocampus, dentate nucleus, substantia nigra, and inferior olivary nucleus. Moderate to severe TDP-43-immunoreactive neuronal cytoplasmic inclusions as well as dystrophic neurites were observed in the frontal, parietal, and temporal cortices, cingulate gyrus, precuneus, thalamus, subthalamic nucleus, hippocampus, entorhinal cortex, and inferior olivary nucleus (Fig. 1B). These findings are consistent with TDP-43 Type A pathology. 2 Tau immunohistochemistry revealed rare neurofibrillary tangles, tau-immunoreactive neurons and neuropil threads in the putamen, substantia innominata, pyramidal layer of the hippocampus, and entorhinal cortex. Alpha-synuclein was absent.Progranulin expression was absent in the frontal and temporal cortices by semiquantitative real-time polymerase chain reaction expression analysis (Fig. 1C) and strongly reduced in the inferior frontal (216 fold reduction) and temporal lobes (25.7 fold reduction).In the family, the variant (and low progranulin plasma levels) segregated with dementia ( Fig. 1D): a sister diagnosed with frontotemporal dementia at 72 years of age, and another with language impairment and gait imbalance at 74 years of age (II:1, II:3). One sister without the GRN mutation developed Parkinson's disease without cognitive impairment (after 8 years from onset) at 53 years (II:6). Another sister (II:2) had clinical amnestic mild cognitive impairment, 3 but did not convert to dementia at 18 months of follow-up.In conclusion, rapidly progressive nvPPA and parkinsonism was associated in this patient with the novel GRN mutation g.1642_1645delTGAG (IVS711delTGAG). We showed that this variant segregates with dementia in the family and is associated with reduced progranulin plasma levels and TDP-43 histopathology.

Expanding the Spectrum of Dopa-Responsive Dystonia (DRD) and Proposal for New Definition: DRD, DRD-plus, and DRD Look-alike

“…Rauschendorf et al 28 reported two siblings with generalized dystonia. They had the histories of seizure in the childhood.…”

“…Several neurodegenerative disorders affecting dopamine system can present with dystonias responsive to dopaminergic drugs. JPD (including SYNJ1 mutation), 24 25 26 27 28 PPS, 29 30 and SCA3 31 are good examples. They have frequent parkinsonism, relatively late onset, and progressive disease course with drug-related complications compared to non-neurodegenerative disorders in the dopaminergic system.…”

“…It is associated with parkinsonism, dystonia, hypotonia, resting/action tremor, postural instability, seizure and cognitive impairment. 28 61 The age at onset is around 20 years and the symptoms are progressive. The presynaptic nigrostriatal dopaminergic deficits in DAT scan and levodopa responsiveness for parkinsonism were reported in several cases.…”

“…Some neurodegenerative disorders which involve nigrostriatal dopaminergic system such as juvenile Parkinson's disease (JPD), pallidopyramidal syndrome (PPS), and spinocerebellar ataxia type 3 (SCA3) also mimicked features of DRD or DRD-plus. 24 25 26 27 28 29 30 31 Moreover, there are reports of cases with DYT1 mutation, GLUT1 mutation, myoclonus-dystonia (MD), and ataxia telangiectasia (AT) under the heading of DRD because of their dopa-responsiveness, however, these disorders do not involve nigrostriatal dopaminergic system. 32 33 34 35 …”

New Genes Causing Hereditary Parkinson’s Disease or Parkinsonism

“…One of them had reached developmental milestones late, both had cognitive dysfunction in early adult life. CSF analyses showed signs associated with impairments in dopamine synthesis, including decreased homovanillic acid and tetrahydrobiopterin [58]. …”