Atypical Parkinsonism‐Dystonia Syndrome Caused by a Novel DJ1 Mutation

Abstract

We describe a sporadic case of atypical parkinsonism‐dystonia of subacute onset at the age of 16 years in a male from a consanguineous family. He showed marked orofacial dystonia, levodopa‐induced dyskinesia, and a stereotyped bilateral eye‐pressing movement disorder. We combined Sanger sequencing of candidate genes, homozygosity mapping, and whole‐exome sequencing. A homozygous mutation was identified disrupting a splice site in exon 5 of the DJ1 (PARK7) gene. Clinical details and a video are provided. DJ1 mutations are a rare cause of atypical complex parkinsonism. Exome sequencing is efficacious in identifying the causal gene variant.

There is an expanding list of genetic forms of parkinsonian disorders, some of which are associated with additional features such as dystonia and cognitive impairment.1 Among these, mutations in ATP13A2 or PLA2G6 produce a more complex progressive syndrome whereas cases of Parkin, PINK, and DJ1 have been described to have a relatively more benign phenotype.

The number of patients with DJ1 mutations remains scarce in the literature, with only 15 patients from eight families previously reported (Table 1). In this report, we provide a detailed clinical description of a patient with a newly identified homozygous DJ1 mutation as the cause of a sporadic atypical complex dystonia‐parkinsonism syndrome.

Table 1.

Summary of DJ1 cases reported in the literature

Reference	Age at Onset	Familial	Ethnicity	Mutation	Motor Phenotype	Other Features	Imaging
Van Duijn13	40	Familial	Dutch	Intron 5 deletion	Parkinsonism	Psychosis
	31				Parkinsonism, blepharospasm	Neurosis
	n.d.				Parkinsonism	Neurosis
	27				Parkinsonism, dyskinesia
Bonifati10, 18	28	Familial	Italian	T497C	Parkinsonism, blepharospasm
	35				Parkinsonism	Behavioral disturbance at onset
	27				Parkinsonism	Hallucinations after l‐dopa
Abou Sleiman8	39	Sporadic	Ashkenazi Jewish	M26I	Parkinsonism, early dyskinesia	Anxiety
	36	Sporadic	Afro‐Caribbean	D149A, G78G	Parkinsonism	Anxiety
Annesi9	36	Familial	Italian	c.168_185dup	ALS‐parkinsonism‐dementia	Dementia	SPECT, reduced perfusion in basal ganglia, frontal and parietal lobe
	35
	24
Djarmati11	45	Unknown	Serbian	c.253_322del heterozygous	Parkinsonism, no dyskinesia	n.d.
Hering12	34	Familial	Turkish	G192C	Parkinsonism, dysarthria	Sleep disturbance, depression; normal memory	PET, reduced uptake both striata
Tarantino19	38	Sporadic	Italian	C159G; intron 4 splice site (IVS4 + 3insA)	Parkinsonism
Our case	15, subacute	Sporadic	Kurdish	Homozygous deletion in the splice site for exon 5	Parkinsonism, dystonia, stereotypies, spasticity, anarthria, severe dyskinesia		MRI, superior cerebellar vermis atrophy

n.d., no data available.

Case Report

The proband is a 20‐year‐old man of Kurdish ancestry who is the product of a consanguineous marriage (his parents are first cousins). His mother said she was exposed to chemical warfare in northern Iraq during his pregnancy. He had an uncomplicated birth and his initial early motor milestones were delayed secondary to congenital hypothyroidism. On initiation of levothyroxine replacement, he caught up with all his developmental milestones and attended mainstream school until symptom onset.

At the age of 16, over a period of 4 to 6 weeks, he developed a levodopa‐sensitive parkinsonian syndrome characterized by tremor, bradykinesia, and gait difficulty. He required a wheelchair from that point and became totally dependent. He developed severe dysarthria and bladder dysfunction with urinary frequency. Cognition remained unimpaired, but he had low moods and was aggressive at times. Vision and hearing remained normal and he was able to enjoy play station video games and iPad games. There was no family history of neurological disease.

On examination at age 20, during an “OFF” period (see Video, Segment 1) he had a facetious dystonic smile, with his mouth open, occasional arrythmic movements of his upper lip, and a rhythmic tongue tremor. He was severely dysarthric. His saccades were slightly hypometric, but eye movements were otherwise normal. There was marked rigidity, bradykinesia on repetitive movements, and bilateral 5‐ to 6‐Hz rest and postural hand tremor with dystonic posturing and some superimposed myoclonic jerks. When emotionally excited, he performed a stereotyped complex movement where he would hold both his semiclenched hands rigidly over his eyes as if rubbing his eyes with his knuckles similar to “eye‐pressing” blindisms2 (see Video, Segment 2). His mother said these movements only occurred 2 years after disease onset when he had to join a special school, which she attributed to him mimicking other children in a special school.

Deep tendon reflexes were brisk with upgoing plantars. There were no cerebellar or sensory signs. He was unable to walk.

Routine blood tests were normal, including blood counts, C‐reactive protein, glucose, folic acid, thyroid and liver function tests, plasma and urinary copper studies, iron, and an autoantibody screen. Genetic testing was normal for Huntington disease and spinocerebellar ataxia (SCA)1, SCA2, SCA3, SCA6, and SCA7. An MRI scan of the brain, including gradient echo sequences, was essentially normal other than a hint of superior cerebellar vermis atrophy.

He developed severe peak‐dose dyskinesias, even on small doses of l‐dopa (<50 mg daily) and was switched to a dopamine agonist. However, it is unclear if he derived definite benefit from the dopamine agonist.

Patient and Methods

Consent was obtained from the patient and his mother for DNA extraction and genetic sequencing for research purposes as well as video recording for research and academic publication. Blood samples and consent were also obtained from his two sisters and his mother.

Exome sequencing was performed with the assumption that with the consanguinous history, the disorder was the result of a recessive mode of inheritance. Genomic DNA was prepared according to Illumina'sTruSeq Sample Preparation v3 (Illumina, Inc., San Diego, CA) and capture was performed with Illumina'sTruSeqExome Enrichment, according to manufacturer's instructions. Sequencing was performed in Illumina'sHiSeq 2000 using 100‐bp paired‐end reads. Following quality control procedures, the index case sample yielded over 8.4 billion bases of high‐quality, aligned data. This amount of data represented a mean coverage of all targeted regions of 71.9×, percentages of targets covered at greater than or equal to 10× of 93.4% and less than 1% of targets not being covered at least once. Sequence alignment and variant calling were performed against the reference human genome, hg19 assembly3 using BWA4 and the Genome Analysis Toolkit.5 Polymerase chain reaction duplicates were removed before variant calling using Picard software (http://picard.sourceforge.net/index.shtml). Based on the hypothesis that the mutation underlying this rare familial disease was not present in the general population, we excluded all common single‐nucleotide polymorphisms (SNPs) identified in the 1000 Genomes Project6 or in dbSNP.7 Sanger sequencing was used to confirm the presence of the mutation in the proband and, in the limited immediate family available, to confirm segregation.

Results and Discussion

We identified a unique homozygous deletion in DJ1 (NM_001123377:c.317_322del:p.106_108del) encompassing the 5′ consensus splice site for exon 5, using exome sequencing; this mutation is likely to result in truncation of the protein (Fig. 1). One of the siblings was found to carry the same mutation in a heterozygous state, whereas the other one did not carry the mutation, supporting the hypothesis that the mutation is inherited in an autosomal recessive fashion.

Figure 1.

Figure representing the homozygous deletion found at the PARK7 locus. Shown is the 5′ end of exon 5 with 11 bases deleted. The deletion occurs in a sequence that is partially repeated just downstream, with the single difference being the second intronic base T that is substituted by a G when the deletion occurs, thus disrupting the canonical splice sequence.

Compared to previously described mutations in DJ1, where patients had parkinsonism with minimal associated features8, 9, 10, 11, 12, 13 (Table 1), the effect of this newly described mutation is much more severe, with a complex dystonia‐parkinonism phenotype with marked anarthria and dystonia.

The complex dystonia‐parkinsonism phenotype in this case is more typical of disorders such as Wilson's disease, Kufor‐Rakeb syndrome, PLA2G6‐associated neurodegeneration, ATP1A3 mutations, or juvenile Huntington's disease with orofacial dystonia, lingual tremor, and marked generalized dystonia. The subacute onset (a few weeks) in this case is interesting because previous DJ1 cases were slowly progressive and with later onset (average, 34 years; range, 27–45) and makes it similar in timescale to ATP1A3 mutations, which cause rapid‐onset dystonia‐parkinsonism (RDP/DYT12)14, 15, 16 or Kufor‐Rakeb syndrome.17

Our patient performed an unusual stereotypy resembling “eye rubbing” or blindism mainly observed among severely mentally disabled or visually impaired individuals. By history, he had adopted these from other children in his school.

Similar to other early‐onset Parkinson's disease variants, the patient was sensitive to l‐dopa and developed a most severe dyskinesia. In previous cases, psychiatric symptoms, such as mild mood disturbances, appear to be a common feature. Despite the severe clinical picture, MRI imaging was normal, apart from mild superior cerebellar vermis atrophy, and there was no evidence of abnormal brain iron accumulation.

Conclusion

In summary, we provide the first detailed characterization with video of the movement disorder observed in DJ1 mutation. This case also provides the first description of stereotypic eye‐pressing blindism as a movement disorder. DJ1 gene mutations should be considered as an alternative cause for rapid‐onset dystonia‐parkinsonism syndrome if no mutations are found in the ATP1A3 gene.

Funding Agencies

This work was supported, in part, by the Wellcome Trust/MRC Joint Call in Neurodegeneration award (WT089698) to the UK Parkinson's Disease Consortium (UKPDC). R.G. is supported by a fellowship from the Alzheimer's Research UK. S.A.S. was supported by the Else Kroener Fresenius‐Stiftung, the Eva Luise‐und‐Horst Köhler Foundation, Novartis Pharma, and the Bosch Fast Track Stipend.

Acknowledgment

The authors thank Dr. Chinar Osman for assisting in interpreting to the patient and his family.

Author Roles

(1) Research Project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript: A. Writing of the First Draft, B. Review and Critique.

J.M.B.: 1A, 1B, 1C, 3A, 3B

R.J.G.: 1A, 1B, 1C, 3B

J.T.H.T. 1B, 1C, 3A, 3B

L.D.: 1C, 3B

J.V.: 3B

S.M.: 3B

J.H.: 1A, 3B

S.A.S.: 1A, 1B, 1C, 3A, 3B

Financial Disclosures

J.M.B. has been awarded research grants from Wellcome Trust/MRC strategic award (WT089698) and grants from Parkinson's UK and The Bachmann Strauss Foundation and has been employed by University College London (UCL). R.J.G. has been awarded research grants from Alzheimer's Research UK and an Alzheimer's Research UK Fellowship. J.T.H.T. has held stock in Biogen in 2012, but sold this in early 2013; has held a consultancy with the Clinical Unit of GlaxoSmithKline (GSK) Cambridge in 2010 and received an honoraria; has received travel funding support from the Michael J. Fox Foundation and the Kinetics Foundation in 2013 to the Movement Disorders Congress; has been employed by South London Healthcare NHS Trust; and has received royalties from Wiley‐Blackwell for five medical student books and two medical student smartphone Apps. L

J.V. has received honoraria from Acute Internal Medicine and the Ealing Neuropaces MRCP fund and has been employed by Ealing Hospital NHS Trust. J.H. has held a consultancy with Esai; has been awarded research grants from MRC, Wellcome, PDUK, and ARUK; and has been employed by UCL. S.A.S. has been awarded research grants from Else Kröner Fresenius Stiftung, the Bosch Foundation, Novartis Pharma, and the Köhler Foundation; has been employed by the University of Kiel; and has received royalties from OUP.

Supporting information

Video 1. Segment 1: Patient at age 20 during an “OFF” period. He has a facetious dystonic smile, with his mouth open, occasional arrythmic movements of his upper lip, and a rhythmic tongue tremor. He has bilateral 5‐ to 6‐Hz rest and postural hand tremor with dystonic posturing and some superimposed myoclonic jerks. Intermittently, he demonstrates stereotyped complex movements (also see Video, Segment 2) with rubbing of his eyes. There are no cerebellar signs on finger‐nose test. There is bradykinesia on repetitive movements with early fatiguing. Eye movements are normal. Segment 2: Stereotyped bilateral eye‐pressing movement disorder.