Our patient, of pure Southern Chinese ancestry, was previously healthy until 9 May 2002 (at the age of 10 years), when she became clumsy. This was preceded by a self-limited febrile episode a week earlier. The next day, she had dysarthria, drooling, unsteady gait, and poor handwriting. This progressed over 10 days to a state of being unable to speak, swallow, or walk. She was recognized to have a severe dystonic syndrome when assessed by a pediatric neurologist 3 weeks later. By this time, she had made some recovery and was able to walk with assistance and swallow. Investigations were unremarkable, including routine blood tests, cerebrospinal fluid analysis, brain MRI, and EEG. Slit-lamp examination was negative for Kayser-Fleischer rings. She was diagnosed with postviral encephalitis and given levodopa/carbidopa (100/25 mg, 2 tablets three times daily [TID]), but this was ineffective.
The patient was first assessed at the University of Malaya, Kuala Lumpur, in August 2011, at age 19. She had made gains in functional activities (e.g., no longer falling frequently and able to type fairly quickly on a computer). She was eating a normal diet without choking episodes. The patient was a top scorer in her school examinations, and there were no psychiatric manifestations. There was no relevant family history and no parental consanguinity. Her parents were also examined by us and confirmed to be neurologically intact. Examination revealed facial grimacing and jaw-opening dystonia, especially when speaking, severely slurred speech, and antecollis. There was severe and generalized nonpainful dystonia affecting all limbs and the trunk. Her movements were slow, but this was considered to probably be a result of the severe dystonia and there were no other parkinsonian features, such as rigidity or tremor (limb tone at rest was, in fact, reduced; these findings were confirmed by S.-Y.L. and A.E.L.). There was no ataxia, upper motor neuron signs, or abnormalities of eye movements or hearing.
The patient's DNA was analyzed for ATP1A3 mutations, and she was found to have a mutation in exon 17 at cDNA position c.2267G>A (NM_152296.4), resulting in a p.R756H amino acid substitution (NP_689509; laboratory of L.J.O.). Neither of the patient's parents had this mutation. DNA profiling was performed using short tandem repeat (STR) analysis at 15 STR loci (D8S1179, D21S11, D7S820, CSF1PO, D3S1358, TH01, D13S317, D16S539, D2S1338, D19S433, vWA, TPOX, D18S51, D5S818, and FGA) by an accredited national forensics laboratory; this confirmed that the patient was the biological child of the parents in question.
Benzhexol 2 mg TID subjectively reduced limb stiffness and improved speech, but caused sleepiness and dizziness and was stopped. Her condition has remained stable (see accompanying Video 1 from November 2013), with a Burke-Fahn-Marsden Dystonia Rating Scale Movement Scale score of 67, a Disability Scale score of 13; an RDP Severity Scale score of 4; and the following UPDRS scores (largely felt to be a result of the severe dystonia; see Video 1): Total of 55.5, Parts I of 0, II of 16, III of 38.5, and IV of 1; and Montreal Cognitive Assessment score of 29/30.
To our knowledge, the ATP1A3 p.R756H mutation has not been reported in typical adolescent-onset RDP. This mutation has been reported only once previously, in a novel infant-variant (i.e., very young onset) case of RDP with atypical clinical features, who inherited the mutation from her father who had only minor neurological symptoms. These cases thus illustrate that the same ATP1A3 mutation can result in vastly different clinical outcomes. We believe that this is also the first case of RDP to be reported in a patient of pure Chinese ethnicity; the only other Asian cases in the literature were a Korean man and a child of mixed Caucasian-Chinese parentage[5, 6] (a cohort of Chinese patients with AHC and ATP1A3 mutations was reported on recently, but none exhibited an RDP phenotype). Our case resulted from a de novo mutation, highlighting the need to consider a diagnosis of RDP even without a family history of similar illness.