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VPS13C-associated Parkinson's disease: Two novel cases and review of the literature

      Highlights

      • Biallelic VPS13C mutations are a definite genetic cause of monogenic Parkinson's disease (PD).
      • Cognitive decline, dystonia, dysautonomia, and pyramidal signs may help to distinguish VPS13C-associated PD.
      • We report two novel VPS13C-associated PD cases carrying three novel VPS13C pathogenic variants.
      • Hearing impairment, oculomotor disturbances, and self-mutilating behaviour are novel phenotypic features.

      Abstract

      VPS13C is a protein-coding gene involved in the regulation of mitochondrial function through the endolysosomal pathway in neurons. Homozygous and compound heterozygous VPS13C mutations are etiologically associated with early-onset Parkinson’s disease (PD). Moreover, recent studies linked biallelic VPS13C mutations with the development of dementia with Lewy bodies (DLB). Neuropathological studies on two mutated subjects showed diffuse Lewy body disease. In this article, we report the clinical and genetic findings of two subjects affected by early-onset PD carrying three novel VPS13C mutations (i.e., one homozygous and one compound heterozygous), and review the previous literature on the genetic and clinical findings of VPS13C-mutated patients, contributing to the knowledge of this rare genetic alpha-synucleinopathy.
      MRI (Magnetic Resonance Imaging), SPECT (Single Photon Emission Computed Tomography), FDG-PET (F-fluorodeoxyglucose Positron Emission Tomography), STN DBS (Deep Brain Stimulation of the Subthalamic Nucleus), PSP (Progressive Supranuclear Palsy)

      Keywords

      VPS13C is a protein-coding gene known to be involved in mitochondrial homeostasis through Pink1/Parkin-mediated mitophagy in response to mitochondrial depolarization [
      • Lesage S.
      • Drouet V.
      • Majounie E.
      • Deramecourt V.
      • Jacoupy M.
      • Nicolas A.
      • et al.
      Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/Parkin-dependent mitophagy.
      ]. Biallelic VPS13C mutations cause a distinct form of early-onset Parkinson's disease (PD), characterized by rapid and severe disease progression, early cognitive decline, dystonic features, pyramidal signs, and neuropathological findings consistent with diffuse Lewy body disease [
      • Lesage S.
      • Drouet V.
      • Majounie E.
      • Deramecourt V.
      • Jacoupy M.
      • Nicolas A.
      • et al.
      Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/Parkin-dependent mitophagy.
      ]. In addition, recent studies suggested that rare biallelic VPS13C variants are also a genetic cause of Dementia with Lewy Bodies (DLB) [
      • Kobayashi R.
      • Naruse H.
      • Koyama S.
      • Kawakatsu S.
      • Hayashi H.
      • Ishiura H.
      • et al.
      Familial dementia with Lewy bodies with VPS13C mutations.
      ,
      • Smolders S.
      • Philtjens S.
      • Crosiers D.
      • Sieben A.
      • Hens E.
      • Heeman B.
      • et al.
      Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson's disease.
      ]. Here we aim to describe two cases of early-onset PD carrying novel VPS13C mutations and review the existing literature on genetic and clinical features of VPS13C-associated alpha-synucleinopathy.
      The first case is a 55-year-old female, daughter of consanguineous parents (Fig. 1A). The eldest brother of the proband was affected by rapidly worsening parkinsonism, which started when he was 44 and was complicated by cognitive deterioration, hallucinations, severe psychomotor agitation, and violent behaviour. Institutionalized and bedridden, he died of pneumonia when he was 52. At the age of 42, the proband manifested hyposmia and slightly progressive bradykinesia of the left limbs. She performed a 123I‐ioflupane SPECT, which showed severe symmetrical dopaminergic denervation (Fig. 1B). A dopamine agonist (pramipexole) was initiated and it was initially effective and well-tolerated, however, it was soon discontinued due to drug-induced visual hallucinations. Levodopa was then started with good initial motor benefit but with rapid development of motor fluctuations and dyskinesias. In addition, she developed urinary urgency, symptomatic orthostatic hypotension, and frequent falls. A bilateral sensorineural hypoacusia became apparent at that age. On neurological examination (Video part 1) she showed continuous vocalizations and echolalia. Hypomimia, limitation of the downward vertical gaze, and oculomotor apraxia were also appreciated. Vertical eye movements were conserved when prompted by Doll's eyes maneuver, suggesting a supranuclear origin of the gaze palsy. Plastic hypertonia of the neck and limbs was present. Cortical release reflexes, such as snout and palmo-mental, as well as masseter reflex were elicitable. Pull test was positive. The gait was unsteady, wide-based, and slow. Sub-continuous choreodystonic dyskinetic movements of the hands were observed, associated with lips self-mutilations. The proband underwent an extensive assessment, including a brain MRI scan, displaying only a moderate frontal cortical atrophy without midbrain atrophy, an FDG-PET (normal), and neuropsychological evaluation, which disclosed an important ideomotor slowing with memory, attention, and executive deficits, associated with oculomotor and ideomotor apraxia. A lumbar puncture was performed, revealing normal levels of Tau, Phospho-Tau, Aβ1-42, and 14-3-3 proteins. The parkinsonism progressed and at last examination she showed a stuporous, progressive supranuclear palsy-like face, with a complete downward vertical gaze paralysis and worsening of oculomotor and limbs apraxia (Video part 2). Genetic analysis showed the presence of a novel homozygous frameshift VPS13C mutation c.860_866dupATATACC predicted to code a highly deleterious early protein truncation (p.Pro290Tyrfs*45) (NM_020821) (Fig. 1C).
      Fig. 1
      Fig. 1(A) Pedigree of the proband 1 (black filling indicates affected individuals, grey filling denotes unspecified late-onset cognitive deterioration); (B) 123I‐ioflupane SPECT imaging of proband 1 shows a symmetrical severe putaminal denervation and a symmetrical reduction of radiotracer uptake in the caudate nuclei; (C) Electropherogram of the identified VPSC13C homozygous c.860_866dupATATACC (p.Pro290Tyrfs*45) mutation in subject 1 compared to wild type sequence; (D) Pedigree of the proband 2; (E) Electropherograms of the three VPSC13C mutations found in subject 2: c.532delA (p.Lys178=fs*12), c.4669G>C (p.Ala1557Pro), and c.7806C>G (p.Tyr2602*); (F) Graphical representation of the Vps13c protein domains and the pathogenic mutations reported so far.
      The second case is a 43-years-old man without family history of movement disorders (Fig. 1D). Past medical history showed hearing impairment from the age of 18 years. He presented with painful dystonic dorsal flexion of the right big toe after moderate physical activity. One year after he showed bradykinesia affecting his right arm, micrography, and mild depression. At the age of 45 years, he started taking levodopa with good control of motor symptoms, except for foot dystonia. At the age of 48 years, he underwent the following investigations: 123I‐ioflupane SPECT, which disclosed significant bilateral reduction in dopamine in the putamen and caudate; brain MRI, which showed only mild cortical cerebellar atrophy and mild parietal cortical atrophy in the left cerebral hemisphere; Mini Mental State Examination (MMSE), which was within the normal range (28/30). At the age of 49 years, he reported progression of his symptoms, with nocturnal akinesia, hypomimia, Pisa syndrome, wearing off, and forgetfulness. Rapid Eye Movement Sleep Behaviour Disorder (RBD), snoring and daytime sleepiness appeared. Urine and faecal urgency became manifest. Neuropsychological assessment disclosed severe deficits in language, memory, and executive functions (Supplementary Table 1). He was treated with rivastigmine and memantine with only temporary and subjective benefits. At 55, he was no longer able to stand and walk independently and he needed a wheelchair. At the age of 58, he was bedridden, unable to speak, and a percutaneous endoscopic gastrostomy (PEG) tube was placed due to severe dysphagia. Genetic analysis identified three rare variants: c.532delA (p.Lys178=fs*12), c.4669G>C (p.Ala1557Pro), and c.7806C>G (p.Tyr2602*) (Fig. 1E). The c.7806C>G and c.532delA are novel, while the c. 4669G > C is a known extremely rare variant of unknown significance (rs201577653). The frameshift substitution (c.532delA) is expected to lead to a premature stop codon (p.Lys178=fs*12). Conversely, the c.7806C > G is predicted to trunk the VPS13C protein at the amino acid position 2602 (p.Tyr2602*). Segregation analysis showed that the c.532delA (p.Lys178=fs*12) and c.4669G>C (p.Ala1557Pro) were associated in cis and derived from the father, while the c.7806C>G (p.Tyr2602*) originated from the mother.
      To date, only 16 clinically described cases of VPS13C-related PD cases have been reported in the literature [
      • Lesage S.
      • Drouet V.
      • Majounie E.
      • Deramecourt V.
      • Jacoupy M.
      • Nicolas A.
      • et al.
      Loss of VPS13C function in autosomal-recessive parkinsonism causes mitochondrial dysfunction and increases PINK1/Parkin-dependent mitophagy.
      ,
      • Hopfner F.
      • Mueller S.H.
      • Szymczak S.
      • Junge O.
      • Tittmann L.
      • May S.
      • et al.
      Rare variants in specific lysosomal genes are associated with Parkinson's disease.
      ,
      • Kobayashi R.
      • Naruse H.
      • Koyama S.
      • Kawakatsu S.
      • Hayashi H.
      • Ishiura H.
      • et al.
      Familial dementia with Lewy bodies with VPS13C mutations.
      ,
      • Smolders S.
      • Philtjens S.
      • Crosiers D.
      • Sieben A.
      • Hens E.
      • Heeman B.
      • et al.
      Contribution of rare homozygous and compound heterozygous VPS13C missense mutations to dementia with Lewy bodies and Parkinson's disease.
      ,
      • Schormair B.
      • Kemlink D.
      • Mollenhauer B.
      • Fiala O.
      • Machetanz G.
      • Roth J.
      • et al.
      Diagnostic exome sequencing in early-onset Parkinson's disease confirms VPS13C as a rare cause of autosomal-recessive Parkinson's disease.
      ,
      • Darvish H.
      • Bravo P.
      • Tafakhori A.
      • Azcona L.J.
      • Ranji-Burachaloo S.
      • Johari A.H.
      • et al.
      Identification of a large homozygous VPS13C deletion in a patient with early-onset Parkinsonism.
      ,
      • Gu X.
      • Li C.
      • Chen Y.
      • Ou R.
      • Cao B.
      • Wei Q.
      • et al.
      Mutation screening and burden analysis of VPS13C in Chinese patients with early-onset Parkinson's disease.
      ] (Supplementary Table 2, Fig. 1F). From the review of the literature and the two cases described here, it emerges clearly that VPS13C-related parkinsonism is characterized, with only few exceptions [
      • Kobayashi R.
      • Naruse H.
      • Koyama S.
      • Kawakatsu S.
      • Hayashi H.
      • Ishiura H.
      • et al.
      Familial dementia with Lewy bodies with VPS13C mutations.
      ], by the classical motor (bradykinesia, rigidity, rest tremor, freezing, postural instability) and non-motor clinical features of PD (dysautonomia, cognitive decline, visual hallucinations, and hyposmia). The clinical response to dopaminergic therapy appears to be favourable in most cases. Motor fluctuations and levodopa-induced dyskinesias are common. A single VPS13C-mutated patient underwent STN DBS, with clinical benefit. The age at onset is earlier in comparison to the idiopathic form (mean age at onset: 37.5 ± 10.5 years). The clinical progression appears to be generally faster. In addition, several associated motor features can be present, such as dystonia and, less frequently, pyramidal signs. Progressive cognitive deterioration is present in most cases. Brain MRI can show symmetrical or asymmetrical lobar atrophic changes without a clear basal ganglia involvement. 123I‐ioflupane SPECT shows features compatible with dopaminergic denervation, often in an asymmetrical fashion.
      The two probands described here exhibited some peculiar phenotypic findings, such as hearing impairment (both subjects), oculomotor disturbances (subject 1), and self-mutilating behaviour (subject 1). Interestingly, the presence of supranuclear gaze palsy, cognitive dysfunction and postural instability in case 1 suggested a PSP-like phenotype, especially in the last years of clinical follow-up. In conclusion, we presented two novel cases and reviewed the existing literature on the clinical and genetic features of VPS13C-associated PD, contributing to the knowledge of this rare monogenic alpha-synucleinopathy.

      Appendix A. Supplementary data

      The following are the Supplementary data to this article:

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