DCTN1-related neurodegeneration: Perry syndrome and beyond

Abstract

Perry syndrome (PS) is a rare hereditary neurodegenerative disease characterized by autosomal dominant parkinsonism, psychiatric symptoms, weight loss, central hypoventilation, and distinct TDP-43 pathology. The mutated causative gene for PS is DCTN1, which encodes the dynactin subunit p150^Glued. Dynactin is a motor protein involved in axonal transport; the p150^Glued subunit has a critical role in the overall function. Since the discovery of DCTN1 in PS, it has been increasingly recognized that DCTN1 mutations can exhibit more diverse phenotypes than previously thought. Progressive supranuclear palsy- and/or frontotemporal dementia-like phenotypes have been associated with the PS phenotypes. In addition, DCTN1 mutations were identified in a family with motor-neuron disease before the discovery in PS. In this review, we analyze the clinical and genetic aspects of DCTN1-related neurodegeneration and discuss its pathogenesis. We also describe three families with PS, Canadian, Polish, and Brazilian. DCTN1 mutation was newly identified in two of them, the Canadian and Polish families. The Canadian family was first described in late 1970’s but was never genetically tested. We recently had the opportunity to evaluate this family and to test the gene status of an affected family member. The Polish family is newly identified and is the first PS family in Poland. Although still rare, DCTN1-related neurodegeneration needs to be considered in a differential diagnosis of parkinsonian disorders, frontotemporal dementia, and motor-neuron diseases, especially if there is family history.

1. Introduction

Axonal transport is mediated by a number of microtubule motor proteins and is fundamental to neurons [1]. Deficits in axonal transport contribute to several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease (PD), Huntington’s disease (HD), hereditary neuropathies, and motor-neuron diseases [2]. A direct link between disrupted axonal transport and neurodegeneration has been emphasized by the identification of mutations in the microtubule motors of patients with neurodegenerative diseases [3]. Dynactin is a multi-subunit protein complex that binds and activates dynein, which engages retrograde axonal transport [4]. The dynein-dynactin motor complex conveys cargo in a retrograde fashion along the microtubules. The dynactin subunit p150^Glued, encoded by the DCTN1 gene, has an essential role in binding microtubules and molecular motors, including dynein [4].

Perry syndrome (PS) is a rare neurodegenerative disorder characterized by autosomal dominant inheritance, psychiatric symptoms, parkinsonism, weight loss, and central hypoventilation. DCTN1 is a causative gene for PS [5], but interestingly, a DCTN1 mutation had previously been identified in a family with motor-neuron disease [6]. In addition, rare DCTN1 variants have been found in patients with other neurodegenerative phenotypes, such as amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and progressive supranuclear palsy (PSP)-like syndrome. In this review, we provide current knowledge of PS and discuss the pathogenesis of DCTN1-related neurodegeneration.

2. Ethical standards

The blood specimens from Canadian, Polish, and Brazilian families described in this manuscript were collected under the Institutional Review Board (IRB) Committee approved protocols of the participating institutions. All research subjects signed informed consent. The brain autopsy of the Colombian family index case was performed at the Mayo Clinic Florida after permission obtained from the legal next-of-kin. The Mayo Clinic IRB Committee exempts the autopsy studies from human subject research regulations.

3. Perry syndrome

3.1. From the first clinical description to the discovery of the gene

In 1975, a new neuropsychiatric disorder was described in a Canadian (British Columbia) family by Perry et al [7]. The affected members spanned three generations, and their disorder was passed down via autosomal dominant inheritance [7, 8]. The proband presented with depression, a loss of interest, and withdrawal from society when he was 50 years old. As the disease progressed, he developed fatigue, sleep disturbances, weight loss, and parkinsonian symptoms, such as hypomimia, reduced arm swing, resting tremor, dysarthria, dysphagia, and hypoventilation. None of the drugs typically used for treating neuropsychiatric disorders, including levodopa, benefitted his condition. He died from unexpected respiratory failure at the age of 56 years. His brain showed depigmentation and severe neuronal loss in the substantia nigra; however, no distinct Lewy bodies were seen.

Perry followed this family for over 15 years and identified at least ten affected members with this unique disease. All of these patients essentially developed the same clinical presentation: psychiatric symptoms such as depression and apathy appeared as an early feature, followed by parkinsonism, weight loss, and central hypoventilation (respiratory failure), which could be prominent at the end stage of the disease and the cause of death. Some patients suffered from sleep disturbances, such as insomnia which could have been related to the hypoventilation. Levodopa and antipsychotic therapies usually were not effective in these patients. The mean age of onset was 50 years (n = 10, range: 45–54 years), and the disease duration from onset to death was 5 years (range: 3–6 years).

By 2002, six other families had been reported from Canada (Ontario), the US (West Virginia), France, the UK, Japan (Fukuoka 1), and Turkey [9–15]. These families showed very similar phenotypes and an autosomal dominant pattern of inheritance. Exceptionally, the UK family did not exhibit weight loss or hypoventilation, but other clinical and pathological findings were compatible to that of the original family [13]. Although none of the families were mutually related or had a common ancestor, we hypothesized that a single gene might cause PS based on the uniform and unique phenotype of this disease.

In 2001, an ad hoc international consortium to study PS was established by ZKW with the aim of finding a genetic cause for PS. We collected DNA samples from all but one of the 7 families and from 2 additional families (Japan [Fukuoka 4] and US [Hawaii]) [16, 17]. Unfortunately, we could not obtain any DNA samples from the second Canadian (Ontario) kindred at that time since this family was lost for follow up. Using genome-wide linkage analysis, we identified that a locus on chromosome 2p12–14 was linked to the disease, and finally we discovered DCTN1 as a causative gene for PS in 2009 [5]. Five different mutations of the DCTN1 gene were identified in all 8 families with disease segregation: p.Gly71Arg, p.Gly71Glu, p.Gly71Ala, p.Thr72Pro, and p.Gln74Pro. No common founder was predicted by haplotype analysis. After discovery of the gene, four other PS families with DCTN1 mutations were reported from Korea (p.Gly67Asp) [18], the US (Georgia) (p.Gly71Arg) [19], New Zealand (p.Tyr78Cys) [19], and Colombia (p.Gly71Arg) [19, 20], indicating that PS with DCTN1 mutation could be found worldwide.

3.2 Typical findings of PS

PS is a fatal disease, and the cardinal features of PS are autosomal dominant parkinsonism, psychiatric symptoms, weight loss, and hypoventilation [21]. Typically, parkinsonism and psychiatric symptoms develop in the initial stage of the disease accompanied with or followed by weight loss. Hypoventilation usually appears in the later stage [21]. Levodopa is usually ineffective or has only partial effect for the parkinsonism, and if so in the initial stage of the disease. However, occasionally a substantial beneficial effect can be observed [10, 14, 15]; notably, it is worth trying a high dose of carbidopa/levodopa (>2,000 mg of levodopa per day) if the usual dose does not sufficiently benefit the patient. Psychiatric symptoms mainly manifest as apathy or depression. The weight loss is usually progressive, even if the sufficient nutrition is provided and the extent of the weight loss has been reported to range from 15 kg in 6 years to 10 kg in 2 months. PS-associated central hypoventilation is life-threatening, with the majority of patients dying due to respiratory failure. Polysomnography is useful for detecting central hypoventilation with hypoxia [14], and noninvasive positive-pressure ventilation may be helpful. A successful case treated with a bilateral diaphragmatic pacemaker implantation has been reported [20].

Additional findings that are more similar to PD have been observed in the Japanese families with PS. Impulse control disorders and punding have been reported in two cases from the Japanese (Fukuoka 1) family [22]. These findings might be related to dopaminergic therapy like those seen previously in PD patients. Indeed, one of these patients also had motor complications such as wearing-off and dyskinesia. In another Japanese (Fukuoka 4) kindred, the family members presented with dysautonomia (e.g. orthostatic hypotension, increased urinary frequency, anhidorosis) [17]. A patient from this family showed decreased cardiac metaiodobezylguanidine uptake, which is frequently observed in Lewy body diseases [23], indicating that sympathetic denervation could occur in PS.

No specific findings on brain imaging of PS patients are known. However, striatal dopaminergic and cortical/subcortical serotonergic dysfunctions were indicated by positron emission tomography [18, 24]. Hypoperfusion in the frontal cortex and basal ganglia has also been detected using ¹²³I-single photon emission computed tomography [17], and transcranial sonography revealed hyperechogenicity of the substantia nigra, which is compatible to findings in PD [25].

3.3. DCTN1 mutation in the second Canadian family and in a newly identified Polish family

Very recently, we had the opportunity to evaluate the second Canadian (Ontario) family and found a DCTN1 mutation, p.Gly71Glu, in an affected family member (Figure 1A). Patient IV-2 was one of the daughters of the proband’s identical twin brother, who had been reported as a patient III-7 in 1979 by Purdy et al [9]. Patient IV-2 was admitted to the hospital when she was 57 years old because she had a decreased level of consciousness and had experienced falls. She was found to have hypercapneic respiratory failure and was intubated. A neurological assessment revealed that she had hypometric saccades, facial masking, mild rigidity in her upper and lower extremities bilaterally, hyperreflexia, and positive Babinski signs bilaterally. In the past two years, she became anxious, depressed, and socially withdrawn, which forced her to retire from her job. She also lost a significant amount of weight and fell multiple times during this period. Her symptoms were quite similar to her father who had typical PS. Additionally, her cousin, a daughter of the proband (IV-1), passed away with suspected PS, but we could not gain any detailed information about her.

Figure 1. Pedigrees of a Canadian (Ontario) Family (DCTN1, p.Gly71Glu) and a Polish Family (DCTN1, p.Gly71Glu) with Perry Syndrome.

(A) A Canadian (Ontario) family. This pedigree is generated by combining the original one [9] with the newly obtained information (dashed rectangle). An arrow and an arrowhead indicate the original proband [9] and the new mutation carrier, respectively. The numbers at the left upper side of the symbols indicate pedigree position. (B) A Polish family. An arrow indicates the proband. The numbers at the right lower side of the symbols indicate the age of death. For (A) and (B), the square indicates a male, the circle indicates a female, the diamond indicates a blinded sex. The numbers inside the symbols indicate the number of siblings.

We identified the first Polish family with PS (Figure 1B). A 45-year-old man was initially referred for apathy and bradykinesia. He had been suffering from difficulties in learning, planning, and concentration for last 3 years. He was diagnosed with depression and catatonia by a local psychiatrist who treated him with neuroleptics. Due to the lack of improvement, he was referred to neurology department. Neurological exam revealed mild cognitive impairment, hypomimia, slow speech with dysarthria, severe bradykinesia, more prominent on the left side, and right Babinski sign. He was not able to walk independently. He had difficulty falling asleep. Initially, his parkinsonism was dramatically improved by benserazide/levodopa (1,125 mg of levodopa per day) and ropinirole (8 mg per day). He became ambulatory again. Over the subsequent 3 years, the responsiveness to dopaminergic medications had decreased and his cognitive impairment and parkinsonism gradually progressed. Rest tremor appeared in his left arm. Wearing off and impulse control disorders including increased sexual activity, trichotillomania, compulsive behaviors, and pathological shopping developed. At 3 years after his first visit, he noticed breathing problems and exhibited tachypnea at night. At age of 51 years, he developed acute respiratory failure requiring intubation and supportive ventilation. After recovery, he had two more episodes of acute respiratory failure. At the present time his respiratory problems are managed through nocturnal assisted ventilator support delivered through tracheostomy. He also had dysphagia, oromandibular dyskinesia, restless legs syndrome, and orthostatic hypotension. The “round the houses” sign was observed in his vertical saccades. He experienced an episode of tonic-clonic seizure. Obvious weight loss was not observed. Brain MRI demonstrated only mild cerebellar atrophy. The dopamine transporter imaging showed severely reduced radiotracer uptake in striatum bilaterally. Genetic tests were negative for MAPT, GRN, and C9orf72, but positive for DCTN1, p.Gly71Glu mutation. The pedigree indicates an autosomal dominant inheritance (Figure 1B). Three other family members were diagnosed with atypical parkinsonism and died at relatively young age.

Both families presented with typical PS but weight loss was not obvious in the Polish family. Weight loss is one of the cardinal signs of PS, however, not always reported in previous cases [10, 13, 16]. Interestingly, some symptoms reminiscent of PSP were observed in the patient IV-2 of Canadian family (e.g. hypometric saccades, frequent falls) and in the proband of Polish family (e.g. the “round the houses” sign [26]).

4. Pathology of Perry syndrome

Pathologically, PS is characterized by neuronal loss and gliosis in the substantia nigra (Figure 2). Lewy bodies and neurofibrillary tangles are not present in brains with PS [7–10, 13, 14], however very sparse Lewy bodies had been reported in two Canadian families, a family from the US (West Virginia) and from the UK [7–10]. These observations were made prior to the discovery of α-synuclein and no Lewy bodies have been reported in PS using more specific methodologies. Neurons with focal clearing of cytoplasm or eosinophilic intranuclear inclusions have been reported, but the significance of these findings are unknown [7, 9]. A variable degree of neuronal loss and gliosis is also evident in the caudate nucleus, globus pallidus, subthalamic nucleus, hypothalamus, locus ceruleus, periaqueductal gray matter, ventrolateral medulla, dorsal raphe nucleus, and pontine reticular formation [27]. From an immunohistochemistry analysis of a single autopsied case from a Japanese (Fukuoka 1) family, neuronal loss in the pre-Bötzinger complex of the ventrolateral medulla and serotonergic neuronal loss in the medullary raphe and ventrolateral medulla were found [28]. These latter findings may be responsible for the respiratory failure seen in PS patients.

Figure 2. Neuropathology of Perry Syndrome from the Proband of the Colombian Family (DCTN1, p.Gly71Arg).

This case has been reported previously as the proband of the Colombian family [19, 20]. She died at age of 60 years due to pneumonia. Her cognitive function was preserved until her condition was terminal. a. mild atrophy and brown discoloration of the globus pallidus (GP); b. marked loss of neuromelanin pigment in the substantia nigra (SN); C. axonal spheroids (arrow) and gliosis in the globus pallidus; d. neuronal loss and gliosis in subthalamic nucleus; e. neuronal loss and gliosis in substantia nigra, and cytoplasmic clearing in a nigral neuron; f. TDP-43 positive dystrophic neurites in globus pallidus (upper left inset: neuronal intranuclear inclusion; upper right inset: TDP-43 neuronal cytoplasmic inclusion); g. TDP-43 neuronal cytoplasmic inclusion in subthalamic nucleus; h. TDP-43 neuronal cytoplasmic inclusion in substantia nigra (upper right inset: TDP-43 neuronal cytoplasmic inclusion in locus ceruleus). (bar in g = 50 μm applies to panels c - h)

Shortly before identifying the causative gene, PS was discovered to be a transactive response DNA-binding protein of 43 kDa (TDP-43) proteinopathy [27]. Based on our neuropathological analysis of eight patients with PS from Canadian (British Columbia), American (West Virginia), French, and Japanese (Fukuoka 1) families, abnormal TDP-43-positive neuronal cytoplasmic inclusions, dystrophic neurites, glial cytoplasmic inclusions, and axonal spheroids were identified mostly in the substantia nigra and the globus pallidus [5, 16, 27]. The morphology of the TDP-43 pathology was comparable to those seen in other TDP-43 proteinopathies, such as frontotemporal lobar degeneration with TDP-43 (FTLD-TDP) and ALS; however, the distribution was distinct from these diseases (Figure 2). TDP-43 pathology in PS was present mainly in the extrapyramidal system. The neocortex, hippocampus, and upper and lower motor neurons, which are typically affected in FTLD and ALS, were spared. In addition, abnormal phosphorylated and 25-kDa truncated forms of TDP-43 were detected in the insoluble fraction of the substantial nigra and globus pallidus from PS [27]. Therefore, PS is a unique atypical parkinsonian syndrome that is characterized by TDP-43 proteinopathy.

5. Atypical phenotypes of Perry syndrome

The clinical uniformity of PS led to the identification of affected families and the discovery of a causative gene. Indeed, diagnostic criteria based on the cardinal clinical and pathological features had been proposed before the gene was discovered [21]; however, the clinical picture of PS has been expanding since the gene’s discovery. Newsway et al described a UK PS family with atypical features [29]. The proband displayed disinhibited behavior and PSP-like phenotypes such as early axial rigidity, frequent falls, marked slowing of downward saccades, and progressive midbrain atrophy on MRI scans. This patient also had the cardinal PS features but showed a continuously good response to levodopa. He was initially diagnosed as having FTD with parkinsonism, but PS was considered when he later developed central hypoventilation. This patient was observed to harbor the pathogenic p.Gly71Arg substitution in DCTN1 [29]. Another UK patient initially presented with anxiety and depression followed by hypomimia, nuchal ridigity, slow horizontal saccades, eyelid apraxia, and the applause sign when he was in his mid-40s. This patient had frontal-lobe dysfunction and some episodes of disinhibited behavior. He seemed to be a sporadic case and was suspected to have PSP at that time. He later developed weight loss and hypoventilation and was reported to have PS with a DCTN1 p.Gly67Asp mutation [30].

Additional families showing some degree of frontal lobe dysfunction and supranuclear gaze palsy were also reported from Korea and Japan [18, 31], with the Japanese case displaying frontotemporal atrophy on MRI scan [31]. Caroppo et al then identified a French family carrying DCTN1 p.Gly71Glu by analyzing 19 families with PSP-like phenotypes [32]. This pathogenic mutation segregated with disease in four affected members of a family and interestingly showed intrafamilial variability in the clinical phenotypic presentation: PD, PS, PSP, and the behavioral variant of FTD were observed. In addition, a DCTN1 mutation, p.Lys56Arg, was identified in two Asian patients who were clinically diagnosed as PSP by a comprehensive screening in patients with parkinsonism [33].

Recently, a Portuguese family was reported at the Nineteenth International Congress of Parkinson's Disease and Movement Disorders [34]. The PS in this family was passed down via autosomal-dominant inheritance, and affected members showed frontal lobe dysfunction, staring eyes, eyelid apraxia, oculogyric crisis, frequent falls, insomnia, apathy, and parkinsonism. Weight loss and hypoventilation were not observed in the proband or affected siblings, which was similar to the UK family [13], but at least one other affected relative had severe weight loss and respiratory failure. A DCTN1 p.Phe52Leu mutation was reported in the proband.

To summarize these reports, the atypical findings mainly consisted of PSP-like phenotypes, FTD-like phenotypes, and other features (Table 1). These symptoms are atypical when compared with those of typical PS, but they may be not uncommon. Indeed, some of these atypical findings were described in the early reported PS families including the second Canadian and Polish families reported here (Table 2). Clinical heterogeneity within the mutation carriers of the same family has been reported. Although there is no evidence yet, some genetic modifiers or environmental factors may have a role in the phenotypic variability of PS. It is well-established that both caffeine intake [35] and exercise [36] can modify the disease presentation in parkinsonism and for TDP-43 proteinopathy ATXN2 [37] and TMEM106B [38] are recognized as genetic modifiers of penetrance. To date, no pathological analyses have been conducted on atypical PS cases and as such this remains a clinical phenomenon. In addition, for those rare mutations that lack clear patterns of co-segregation with disease in families, caution must be used when conveying pathogenicity.

Table 1.

Typical and atypical clinical features of Perry syndrome

Typical features

Autosomal dominant inheritance

Psychiatric symptoms (apathy, depression, and social withdrawal)

Parkinsonism

Weight loss

Central hypoventilation

Limited response to L-dopa

Fatigue

Sleep disturbancea

Rapid progression

Atypical features

PSP-like

Supranuclear gaze palsy

Eyelid apraxia

Frequent falls

FTD-like

Cognitive impairment

Frontal lobe dysfunction

Personality and behavioral changes

Others

Oculogyric crisis

Pyramidal signs

Dysautonomia

Good response to L-dopa

FTD, frontotemporal dementia; PSP, progressive supranuclear palsy

^aIncluding difficulty in falling asleep, insomnia, nightmare, sleep walking, and excessive sleepiness

Table 2.

Demographic and clinical findings of Perry syndrome families with DCTN1 mutations

	Country	Mutation	Number of affected member (M)	Age at onset (y)	Age at death (y)	Disease duration (y)	Psychiatric symptomsa	Parkinsonisma	Weight lossa	Central hypoventilationa	PSP-likea	FTD-likea	Positive response to L-dopab	References
Typical PS families	Korea	G67D	3 (0)	53	NA	NA	1	3	1	3	0	0	1	Chung et al (2014)[18]
	US	G71A	6 (2)	47	NA	NA	0	2	0	2	0	0	1	Wider et al (2010)[16]
	Japan	G71A	14 (10)	41	49	6	6	7	5	3	0	0	5	Tsuboi et al (2002)[14], Mishima et al (2015)[22]
	UK	G71A	8 (4)	39	47	4	5	6	0	0	1	0	1	Bhatia et al (1993)[13]
	Canada	G71R	13 (9)	50	53	5	12	9	8	10	0	0	1	Perry et al (1975, 1990)[7, 8], Felicio et al (2014)[24], Wider et al (2009)[27]
	Turkey	G71R	5 (2)	48	52	4	4	3	2	4	0	2	2	Elibol et al (2002)[15], Saka et al (2010)[25]
	US	G71R	5 (1)	49	58	9	1	1	1	1	0	0	1	Tacik et al (2014)[19]
	Colombia	G71R	10 (2)	51	NA	NA	1	2	1	8	0	0	1	Pretelt et al (2014)[20], Tacik et al (2014)[19]
	Canada	G71E	7 (3)	49	47	3	6	5	3	4	1	0	0	Purdy et al (1979)[9]
	France	G71E	8 (3)	49	55	7	6	3	0	6	0	0	0	Lechevalier et alf (1992, 2005)[11, 12]
	Poland	G71E	4 (3)	42	53	NA	1	4	0	1	1	0	1
	US	T72P	7 (4)	48	51	3	5	7	2	3	0	1	5	Roy et al (1988)[10], Wider et al (2009)[27]
	Japan	Q74P	4 (1)	56	59	4	1	3	3	3	0	0	3	Wider et al (2010)[16], Oshima et al (2010)[17]
	New Zealand	Y78C	5 (4)	54	57	4	3	1	1	4	0	0	0	Tacik et al (2014)[19]
Atypical PS families	Japan	F52L	11 (4)	57	65	7	3	6	3	4	1	2	3	Araki et al (2014)[31]
	Portugal	F52L	12 (2)	50	NA	NA	3	3	1	1	3	2	1	Barreto et al (2015)[34]
	Canadac	K56Rd	1 (1)	61	NA	NA	0	1	0	0	1	0	0	Gustavsson et al (2016)[33]
	Taiwan	K56Rd	1 (1)	57	NA	NA	0	1	0	0	1	0	0	Gustavsson et al (2016)[33]
	UK	G67D	1 (1)	mid-40s	NA	NA	1	1	1	1	1	1	1	Aji et al (2013)[30]
	UK	G71R	2 (2)	46	56	NA	1	1	1	1	1	1	1	Newsway et al (2010)[29]
	Korea	G71R	3 (2)	43	55	NA	1	3	1	1	1	0	1	Chung et al (2014)[18]
	France	G71E	8 (NA)	47	52	6	6	8	1	3	2	4	2	Caroppo et al (2014)[32]
	Korea	Y78C	3e (2)	51	52	NA	0	2	0	0	2	1	2	Chung et al (2014)[18]

FTD, frontotemporal dementia; M, male; NA, not available; PS, Perry syndrome; PSP, progressive supranuclear palsy

^aNumber of symptom-positive member in each family,

^bNumber of L-dopa responsive member in each family. The effect varies from limited to significant.

^cChinese origin

^dThese two patients were clinically diagnosed as progressive supranuclear palsy (no autopsy confirmation) without other signs of PS. This variant is to be yet proven pathogenic.

^eNone of them had clinical signs of PS other than parkinsonism.

^fIncludes previously unpublished data provided by Drs. Françoise Chapon and Bernard Lechevalier.

6. Demographic summary of PS with DCTN1 mutation

Twenty-three families exhibiting typical and atypical PS symptoms, including three sporadic atypical PS cases (two of them were clinically diagnosed as PSP [33]), have been reported from various countries (Figure 3, Table 2). DCTN1 mutation has been confirmed in at least one affected member of each family. If we analyzed all available data from clinically affected family members regardless of whether their gene statuses were confirmed or not, the age at onset was 49 ± 6 years (mean ± SD, range: 35–70 years). The age of death was 53 ± 7 years (mean ± SD, range 39–70 years), and the disease duration was 5 ± 3 years (mean ± SD, range 2–14 years). The cumulative incidence was calculated using the onset age of the symptomatic carriers (Figure 4). Half of these patients developed the disease by age of 49 years, and the incidence reached to 90% by age of 58 years. The most common mutation in DCTN1 is p.Gly71Arg, which was identified in families with both the typical and atypical presentation of PS.

Figure 3. DCTN1 mutations in Typical and Atypical Perry syndrome.

(A) Worldwide distribution of families with typical and atypical Perry syndrome carrying DCTN1 mutations. The numbers in the parentheses indicate the number of the families. (B) Schema of p150Glued and DCTN1 mutations. All mutations associated with typical and atypical Perry syndrome are located on exon 2.

Figure 4. Cumulative Incidence of Perry Syndrome.

The cumulative incidence is 50% at the age of 49 years and 90% at the age of 58 years.

7.DCTN1 mutations/polymorphisms associated with other phenotypes

Before the discovery of DCTN1’s causative role in PS, a DCTN1 p.Gly59Ser mutation had been identified in a family with distal spinal and bulbar muscular atrophy, also known as distal hereditary motor neuropathy 7B (HMN7B) [6]. The disorder in this family also had an autosomal dominant inheritance pattern; however, the clinical phenotype was quite different from that of the PS families. In a majority of the affected cases, stridor and shortness of breath caused by vocal-fold paresis initially appeared around 30 years of age (mean age of onset was 34 years, range 23–39 years) [39]. The disease slowly progressed, and the symptoms included facial and distal dominant limb weakness without any sensory disturbances. In one autopsied case, neuronal loss was seen in the hypoglossal nucleus and the ventral horn of the spinal cord, but no pathology in the substantia nigra was described. Immunostaining of the dynactin p50 subunit and the intermediate chain subunit of dynein showed neuronal cytoplasmic inclusions in the hypoglossal nucleus. All affected family members possessed the same mutation. This is currently the only confirmed family with HMN7B and a pathogenic DCTN1 mutation. Recently, a DCTN1 p.Glu340Gly substitution has been found in a Korean patient with pure motor neuropathy. However, pathogenicity of this variant remains unclear because there was no obvious family history and segregation was not established [40].

Although not proven to be pathogenic, several variants of DCTN1 have been identified in both sporadic and familial cases with ALS [41–46]. One familial case who had DCTN1 p.Arg1101Lys variant was a member of a family with ALS and FTD. His sibling who had affected FTD had the same DCTN1 variant [42]. In Guam, a family with ALS/parkinsonism-dementia complex (PDC) was identified to harbor a DCTN1 p.Thr54Ile substitution. In this family, one ALS case and her sibling with PDC carried the p.Thr54Ile substitution; interestingly they also had a heterozygous PINK1 variant [45]. Notably, in addition to the DCTN1 variants, some of the patients carried one or two variants in other ALS-associated genes [46]. Using whole exome sequencing, a DCTN1 variant was identified in three other cases; they were diagnosed as having hereditary sensory and autonomic neuropathy type 1 [47], hereditary motor and sensory neuropathy [48], and a complex neurological disease with a slowly progressive, chronic axonal-distal motor neuropathy and extrapyramidal syndrome [49], respectively. The last case also had variants in the KIF5A and NEFH genes, which have been associated with similar phenotypes as described above including neuropathy, extrapyramidal signs, and ALS. The phenotypes of these non-PS cases mainly consisted of motor-neuron signs unlike those seen in PS, but there was a variation from peripheral neuropathy to FTD.

A genetic screening analysis of DCTN1 in 286 samples from patients with neurodegenerative diseases (156 familial PD, 100 pathologically-confirmed TDP-43 proteinopathies [79 FTLD and 21 Alzheimer’s disease], and 27 clinically diagnosed FTD and ALS patients [8 FTD-ALS, 5 FTD and 14 ALS]) identified 36 novel variants and 19 known polymorphisms [50], including p.Thr1249Ile, which was also identified in an ALS patient and an primary lateral sclerosis patient [41, 51]. However, none of these variants demonstrated complete segregation within families. Additional genotyping analyses for these variants using samples from other independent disease series (440 PD, 374 FTD, and 372 ALS samples) and 435 control samples concluded that DCTN1 variants were not a common genetic risk for PD, FTD, or ALS [50]. Moreover, Stockmann et al identified 24 exonic variants among more than 2,700 mixed samples comprised of 1,708 sporadic ALS, 218 striatal diseases (multiple system atrophy, PSP, and HD), and 778 healthy controls. However, none of them had confirmed segregation in affected family members, and some of them were found in both the disease and control groups [52]. Therefore, with the exception of the p.Gly59Ser mutation seen in the HMN7B family, the pathogenicity of these DCTN1 variants identified in non-PS phenotypes remains to be established.

8. DCTN1-unrelated Perry syndrome

A Japanese family with PS phenotype but without a DCTN1 mutation was reported in 2012 [53]. The proband developed apathy, tremor, rigidity, bradykinesia, weight loss, hypoventilation, and pyramidal signs in her mid-40’s. Levodopa was not sufficiently beneficial, and the disease progressed rapidly. She died within two years of onset due to sudden apnea. A sibling had hallucination and spasticity, and her mother showed rapid-progressive parkinsonism. The clinical picture of the proband fit with that of PS; however, pathological and biochemical analyses revealed that she had a tauopathy comparable to PSP without any TDP-43 pathology. No mutations were identified in DCTN1, but the proband and her affected sibling had an intronic 10 + 14 splice site mutation of MAPT [53]. The affected regions of the proband’s brain were similar to that of brains from patients with PS, eg, the pre-Bötzinger complex of the ventrolateral medulla were impacted, indicating that a TDP-43 proteinopathy caused by a DCTN1 mutation and a tauopathy due to a MAPT mutation can produce the cardinal clinical features of PS.

We have identified a Brazilian family clinically diagnosed as having PS. A proband was 48-year-old man who developed weight loss followed by parkinsonism that was characterized by hypomimia, resting hand tremor (left>right), cogwheel rigidity (left>right), bradykinesia, walking difficulties, bradyphrenia, depression, and apathy. He lost 80 kg of his body weight over a period of 12 months despite having a normal appetite. He was treated with benserazide/levodopa (800 mg of levodopa per day) combined with entacapone and mirtazapine but without improvement. Five years after disease onset, he was totally bedridden. He developed dementia, insomnia, and cachexia. A brain MRI scan showed diffuse cerebral atrophy. His medical history was only notable for epilepsy, which began when he was 20 years old, however, it was well controlled with carbamazepine and clonazepam. His father died at young age of unknown neurological disease indicating possible autosomal dominant inheritance. Molecular genetic testing was performed but revealed no pathogenic variants in exon 2 of DCTN1 or exons 1, 7, and 9–13 of MAPT.

9. The relevance of DCTN1 mutations to neurodegeneration

All nine mutations identified in the 14 typical and nine atypical PS families are clustered in exon 2 of DCTN1 among 32 coding exons. However, while the HMN7B-associated mutation p.Gly59Ser was also located in exon 2, the variants in other phenotypes were found in variable positions in DCTN1 (Figure 3B, Table 3). Exon 2 encodes the cytoskeleton-associated protein, glycine-rich (CAP-Gly) domain of p150^Glued. The CAP-Gly domain is required for enriching dynactin in neurite tips associated with the end-binding proteins EB1 and EB3, which are microtubule-binding proteins [54]. Dynactin accumulation enhances recruitment and sustained engagement of dynein and promotes the retrograde flux from the distal axon [55–57]. The CAP-Gly domain has a ⁶⁷GKNDG⁷¹ motif, which is evolutionarily well conserved and plays a pivotal role in microtubule binding [4, 58, 59]. All of the mutations found in typical/atypical PS and HMN7B were located within or close to the ⁶⁷GKNDG⁷¹ motif. The p.Gly59Ser mutant p150^Glued showed reduced binding affinity for microtubules and disrupted the folding of the CAP-Gly domain, inducing aggregation of the p150^Glued in the cell bodies in vitro [6, 60]. The aggregates were immunopositive for the dynein intermediate chain and were seen in the affected neurons in a HMN7B patient with a p.Gly59Ser mutation [39]. The motor-neuron disease phenotype also developed in both p150^Glued G59S knock-in and transgenic mice [61–63]. Intracellular inclusions seen in these mice consisted of mutant p150^Glued [62]. PS-related mutant p150^Glued proteins (p.Phe52Leu, p.Gly71Arg, p.Gln74Pro, and p.Tyr78Cys) showed reduced microtubule binding, and some (p.Phe52Leu, p.Gly71Arg, and p.Gln74Pro) formed cytoplasmic inclusions in the transfected cells [5, 19, 31]. The dynactin subunit p50- and p62-immunopositive neuronal cytoplasmic inclusions, which were occasionally co-localized with TDP-43, were seen in the substantia nigra in PS [5]. However, functional analyses of the ALS-associated mutant p150^Glued (p.Met571Thr, p.Arg785Trp, p.Arg1101Lys, and p.Thr1249Ile) did not show any deficits. Microtubule binding abilities were preserved in all these mutations, and no aggregations were observed in the mutant-overexpressed culture cells [52, 64].

Table 3.

DCTN1 variants in other phenotypes

Exon	Varianta	Phenotypes	References
2	T54I	ALS, PDC	Steel et al (2015)[45]
2	G59R	ALS	Liu et al (2014)[44]
2	G59S	HMN7B	Puls et al (2003, 2005)[6, 39]
3	S111C	ALS	Cady et al (2015)[46]
8	I196V	ALS	Cady et al (2015)[46]
10	E340G	Inherited peripheral neuropathy	Nam et al (2016)[40]
12	D424H	Hereditary sensory and autonomic neuropathy	Klein et al (2014)[47]
16	M571T	ALS	Münch et al (2004)[41]
17	Y670F	Hereditary motor and sensory neuropathy	Schabhüttl et al (2014)[48]
21	R785W	ALS	Münch et al (2004)[41]
23	I935M	ALS	Cady et al (2015)[46]
25	R997W	ALS	Takahashi et al (2008)[43]
26	R1049Q	ALS	Cady et al (2015)[46]
28	S1080F	ALS	Cady et al (2015)[46]
28	R1101K	ALS, FTD	Münch et al (2005)[42]
32	T1249I	ALS, PLS	Münch et al (2004)[41], Cady et al (2015)[46], Mitsumoto et al (2015)[51]
32	H1270Q	ALS	Cady et al (2015)[46]
32	R1275C	Distal motor neuropathy with ataxia and an Extrapyramidal syndrome of tremor and focal dystonia	Daud et al (2015)[49]

ALS, amyotrophic lateral sclerosis; FTD, frontotemporal dementia; HMN7B, hereditary motor neuropathy 7B; PDC, parkinsonism-dementia complex; PLS, primary lateral sclerosis

^aNot yet proven to be pathogenic except G59S.

Given the distinctly different phenotypes of PS and HMN7B, there may be a certain mechanism by which specific cell types, dopaminergic neurons or motor neurons, are damaged preferentially in each disease. Structural analyses revealed that HMN7B-related p.Gly59Ser was located in the center of the CAP-Gly domain, while PS-related mutations were surface-exposed, suggesting that these mutations could lead to different phenotypes depending on their locations [55, 65]. Although a precise mechanism discriminating between both is unknown, mutation-dependent phenotypic differences were observed in vitro and in vivo. HMN7B mutant was more prone to aggregation than PS mutants, and HMN7B mutant had decreased interactions with dynein, suggesting HMN7B mutation affected the confirmation and stability of the mutant protein [55]. When the HMN7B mutant was overexpressed in primary dorsal root ganglion neurons, the insufficient association with dynein resulted in disruption of transport of cargo throughout the axon. In contrast, PS mutants can associate with dynein similar to the wild-type and did not alter the axonal transport itself. However, a reduction in distal dynactin enrichment was caused by impaired binding of mutant p150^Glued to EBs, leading to a decrease the retrograde flux of PS mutants [55]. In a transgenic fly model, aggregates of mutant p150^Glued in the cytoplasm of the motor neurons and the accumulation of dynein heavy chains at the synaptic termini were observed only when HMN7B mutant was overexpressed, but this was not the case for PS mutants [56].

The mechanism by which PS-related DCTN1 mutations induce TDP-43 proteinopathies remains unclear. Given that dynactin/dynein play a role in retrograde transport of autophagosomes [66], one hypothesis is that a disruption of the retrograde transport of lysosomes and autophagosomes may lead to accumulated and aggregate pathological proteins in the soma [3]. Xia et al. showed that a loss of TDP-43 decreased the expression of DCTN1, leading to the inhibition of autophagosome-lysosome fusion in TDP-43-depleted cells. As a result, the accumulation of autophagic cargo induced neurotoxicity [67]. The loss of function of the DCTN1 protein might result in such a vicious cycle in affected cells and contribute to TDP-43 accumulation. Similarly, dynein mutations also impair autophagosome-lysosome fusion and cause the aggregation of pathological proteins [68]. These observations indicated that functional loss of molecular motors associated with axonal transport and/or intracellular trafficking might induce protein aggregation in the cytoplasm.

10. Conclusion

DCTN1 mutations have been identified in several neurodegenerative diseases, indicating that the deficits in axonal transport play a crucial role in the development of neurodegeneration. Although not always confirmed, the pathogenicity of the PS/HMN7B-related mutations is well established. Interestingly, closely located mutations in the CAP-Gly domain of p150^Glued can cause different cell-type specific neurodegeneration, leading to clinically distinct disorders. PS can mimic PSP and FTD, and HMN7B partially resembles ALS; therefore the diagnosis of DCTN1-related neurodegeneration should be in differential diagnosis for patients presenting with neurodegenerative phenotypes, especially in familial cases. In addition, other genes like MAPT might be associated with PS phenotype. Further studies are needed to find a therapy for DCTN1-related neurodegeneration based on the phenotype-specific mechanisms.

Highlights.

• Twenty-three families with Perry syndrome due to DCTN1 mutation have been reported

• Patients with DCTN1 mutations can exhibit diverse phenotypes

• Atypical findings of Perry syndrome consisted of PSP-like and FTD-like phenotypes

• DCTN1 mutation was found in the Canadian family which was first described in 1979

• We identified the first Polish family with Perry syndrome

Abbreviations

ALS

amyotrophic lateral sclerosis

DCTN1

dynactin 1

FTD

frontotemporal dementia

HMN7B

distal hereditary motor neuropathy 7B

MAPT

microtubule-associated protein tau

PD

Parkinson disease

PS

Perry syndrome

PSP

progressive supranuclear palsy

TDP-43

transactive response DNA-binding protein of 43 kDa