Parkinsonism‐dystonia‐2: Case‐series study from Saudi Arabia

Abstract

Parkinsonism‐dystonia‐2 PKDYS2 is an autosomal‐recessive disorder, caused by pathogenic biallelic variants in SLC18A2 which encodes the vesicular monoamine transporter (VMAT2) protein. PKDYS2 is a treatable neurotransmitter disease, and the rate of diagnosis of this disorder has increased significantly with the advance of genomic technologies. Our report highlights a novel pathologic variant in one case and a novel finding on MRI Brain, consisting of a normal symmetrical signal intensity in the dorsal brainstem and pons, and it substantiates the significance of genetic testing in the evaluation of children with developmental delays, which influences clinical decisions to enhance patient outcomes.

Introduction

Parkinsonism‐dystonia‐2 (PKDYS2) (OMIM 618049) is a complex, autosomal‐recessive disorder. It is characterized by global developmental delay, Parkinsonism, dystonia, and autonomic dysfunction. ⁷ The disorder is caused by pathogenic variants in SLC18A2 (193001)⁷ resulting in an impairment of VMAT2, which is involved in the ATP‐dependent vesicular transport of biogenic amine neurotransmitters, ⁷ including dopamine, gamma‐aminobutyric acid (GABA), norepinephrine, serotonin, and histamine, into synaptic vesicles, ² . ⁵ Disease features are consistent with decreased levels of monoamine neurotransmission. ⁶ Treatment with a dopamine receptor agonist results in sustained clinical improvement. ⁷

Since the report of the first case in 2013, more patients have been diagnosed with this condition, expanding the phenotype spectrum and contributing to a deeper level of understanding of dopamine and serotonin transmission which affects brain development. ¹ , ³ , ⁴ This case‐series describes new PKDYS2 cases and sheds light on the impact of precision medicine on treatment. Here, we describe four patients and their responses to treatment. We also describe previously unreported magnetic resonance imaging (MRI) findings that can help define disease characteristics.

Subjects and Methods

Case one: A 15‐month‐old boy, born at term, following an uncomplicated pregnancy and delivery. Parents are cousins (Fig. 1A). At age 4 months, he developed hypotonia, motor regression, and paroxysmal events of generalized dystonic posturing with upward gaze deviation, while awareness is preserved. He had profound, unexplained sweating (Fig. 1B). He had oro‐lingual incoordination. His neurological examination confirmed hypotonia and global developmental delay. He was investigated for seizures; his electroencephalogram (EEG) was normal. Exome sequencing (ES) at the age of 1 year revealed a homozygous pathogenic variant in SLC18A2 (c.710C>A; p. Pro237His) confirming the diagnosis of PKDYS2. Serum serotonin level was 112 nmol/L (380–1300); urine homovanillic acid (HVA) was 11.2 umol/mmol of Cr. Brain MRI showed bilateral symmetrical abnormally high T2 signal intensity with corresponding restricted diffusion in the dorsal brainstem and pons (Fig. 1C).

Figure 1.

Panel A depicts the family pedigree. Circles denote female family members, squares male family members, black symbols affected family members, double bar indicates consanguinity. Panel B shows the profound unexplained sweating in case1, a child with PKDYS2. Panel C shows magnetic resonance imaging MRI for case 1, it shows bilateral symmetrical areas of abnormally high T2 signal intensity with corresponding restricted diffusion within the dorsal brainstem and pons.

He was started on pramipexole (0.005 mg/kg/day divided TID) after the diagnosis was established, and there was witnessed improvement in the dystonic posture. When the dose was increased to 0.01 mg/kg/day, parents reported worsening hypotonia, irritability, and sleep difficulty. Given this, trihexyphenidyl and 5‐hydroxytrptophan were added on his last visit.

Case two: a 10‐year‐old girl, suffering from abnormal head movements, difficulty walking, and frequent falls. Pregnancy and birth history were uncomplicated. Parents are cousins (Fig. 1A). She had developmental regression observed at age 4 months, she learned to sit at age 1 year, walked independently at 2 years, and first words at 2.5 years. She has poor motor planning, left torticollis, and a dystonic gait with intermittent in‐toeing of the right foot. She could climb stairs with support and ride a bicycle with training wheels. She is able to speak complex sentences with no difficulties in pronunciation, but her voice is hypophonic. She attends school with good performance but has challenges with writing. She had paradoxical episodes of repetitive, rhythmic head movements to the left that became worse when she was tired or stressed.

Investigations, including assessing the complete blood count (CBC), hepatic and renal function tests, ammonia, lactate, uric acid, very long chain fatty acid (VLCFA), creatinine kinase (CK), adrenocorticotropic hormone (ACTH), and cortisol levels, were normal. MRI brain conducted twice showed bilateral symmetric periventricular deep white matter T2 hyperintensities. Whole exome sequence (WES) identified a homozygous mutation in SLC18A2, c.1160C>T p. (Pro387Leu), confirming the diagnosis of PKDYS2.

She was started empirically on L‐DOPA‐CARBIDOPA (Sinemet) up to 8 mg/kg/day, divided three times per day, and demonstrated a slight improvement. After the diagnosis was established, she was switched to the direct dopamine receptor agonist pramipexole 0.18 mg twice daily in addition to Baclofen 10 mg twice daily. She experienced a significant improvement evident in the resolution of the head tilt and the dystonia, as well as further improvements in gait and speech. At age 12, she developed some behavioral issues as a known side effect of a direct dopamine receptor agonist, so the dose of pramipexole was reduced and Sinemet was added to the treatment regimen. She continues to elicit progress in motor and cognitive skills on follow‐up assessments.

Case three: an 8‐month‐old boy, with generalized hypotonia, motor regression, and oculogyric crisis since age 4 months. Parents are cousins (Fig. 1A). He has poor head control and frequent oculogyric crises. Workup constituted a normal MRI brain, EEG, and basic hematology and chemistry. At the age of 9 months, he was tried on L‐DOPA‐CARBIDOPA for a few weeks, he developed facial dyskinesia in addition to choreiform movements of the trunk, which stopped upon stopping the L‐DOPA‐CARBIDOPA. WES identified a homozygous pathogenic variant in SLC18A2, c.710 C>A p. Pro237His. In addition, two heterozygous variants in two different genes were found: CACNA1E, c.3214G>A p. Val1072Ile, and KMT2D, c.13839+3C>A (PMID:26497564, PMID 28716265). Pramipexole was given for almost 1 year; the parent‐reported minimal improvement initially, upon incrementing the dose, he developed a hyperkinetic movement disorder, including facial dyskinesia, which improved rapidly with dose reduction. Pramipexole was weaned off by the parents. Currently, he has severe motor and speech delays. He has poor head control, he rarely rolls over. He can reach out to hold objects but is unable to transfer them; he has no words yet but makes meaningless, non‐specific sounds. He has severe axial hypotonia and recurrent generalized dystonia.

Case four: a 5‐year‐old girl presented with recurrent attacks of abnormal tonic posturing, associated with up‐rolling of the eyes for 2 min with preserved awareness, onset at 5 months of age. She also had failure to thrive and a severe global developmental delay. Parents are cousins (Fig. 1A). Investigation assessed levels of ammonia, lactate, uric acid, CK, and hemoglobin electrophoresis. She underwent a nerve conduction study which was normal. EEG and MRI head were normal. SMN1 gene testing was normal. She was treated with carbamazepine for the paroxysmal events of posturing described above, assuming they were ictal events despite no ictal electrographic correlation. WES identified a homozygous deleterious pathogenic variant in SLC18A2, c.829_834+2del, confirming the diagnosis of PKDYS2. This child demonstrated extreme sensitivity to L‐DOPA; on pramipexole 0.06 mg once per day (0.01 mg/kg/day), she elicited hyperkinetic movement disorder and facial dyskinesia. She had frequent and prolonged admissions with aspiration pneumonia and sepsis; she is currently G‐tube fed and tracheostomized, using home oxygen. Pramipexole was stopped by the primary care physician due to the facial dyskinesia, and insomnia, with a plan to reinstate it at 50% of the suggested starting dose when she recovers from the acute illness. Carbamazepine was stopped as the tonic posturing during the acute illness was dystonia and not tonic seizures; she was also started on Clobazam 2.5 mg po every 12 h and Clonidine 0.1 mg/ml every 12 h for blood pressure instability. She responded to Clonidine, but when it was stopped, the hyperkinetic movement got worse, during the acute illness Pramipexole was stopped, and at complete recovery 6 months later the treatment regimen was modified, guided by the molecular genetic diagnosis, Carbamazepine and Clobazam were weaned off, Clonidine was stopped and she was started on Pramipexole, she is tolerating this dopa direct agonist at a much lower dose and a very slow incrementing schedule, she currently has no dystonia or oculogyric crises, sleep remains a challenge, she remains awake for 24–36 h and then sleeps for 12 h, she is more aware and interactive during wakefulness, follow‐up assessments are scheduled to document motor and cognitive development.

Discussion

The first patient cohort with PKDYS2 was reported in 2013 in a large family, who presented with a pathogenic variant in SLC18A2 leading to a p387L amino acid change. ⁷ More patients were identified over the past decade, adding to the spectrum of phenotype presentation and the depth of understanding of the physiology of dopamine transmission.

In this report, we describe new MRI findings, which may help localize where the defective transmission is, we also report a novel deleterious variant in SLC18A2 with a severe phenotype, poor response to treatment, and extreme hypersensitivity to L‐DOPA, this report also intensifies the impact precision medicine has on guiding treatment. Early diagnosis and treatment have a transformational effect on the developmental trajectory of most neurotransmitter diseases, ¹ precise diagnosis will guide treatment decisions and prevent harmful therapies given to children due to inaccurate clinical diagnosis. For example, patients with oculogyric crises and dystonia can be clinically diagnosed with epilepsy and unnecessarily treated with antiepileptic drugs, even though there is no ictal EEG correlation. A recent cross‐sectional study of clinician‐reported outcomes in patients with epilepsy provided evidence in support of the impact genetic studies have on medical management decisions, it confirmed that genetic diagnosis was associated with changes in clinical management in 49.8% of patients. The most common clinical management changes were the addition of a new medication (21.7%), the initiation of medication (14.2%), and the cessation of medication (11.7%). ⁸ These findings address the benefits of genetic testing for all orphan diseases.

In conclusion, our report confirms the importance of genetic testing in the clinical evaluation of children presenting with developmental delays. Accurate diagnosis helps create personalized treatment protocols.

Author Contributions

Each author contributed to the clinical write up of their case. Dr. Alkhater was directly involved in patient care, and wrote the manuscript and the discussion points to highlight the novel points and add richness to the literature.

Conflict of Interest

None.

Funding Information

There is no funding source for this work, this is a clinical paper by the individual efforts of the physician.