Oculogyric Crisis in a Girl with Infantile Parkinsonism-Dystonia-2

Dear Editor,

A 1-year-old girl baby first-born of non-consanguineous parentage, presented with global developmental delay, floppiness of the body, and paroxysmal multiple episodes of involuntary upgaze with preserved awareness lasting for 5–6 h since 4 months of age [Video 1]. There was no history of seizures, sleep disturbances, autonomic dysfunction, tremors, or any drug intake. Her antenatal and perinatal history was normal. She has neck control, can sit without support, immature pincer grasp, speaks monosyllables but does not stand without support, and wave bye-bye. There was no family history of Parkinsonism and there were no other affected siblings. On examination, the child had an intermittent oculogyric crisis, microcephaly, axial hypotonia, and peripheral hypertonia, limb dystonia, and brisk deep tendon reflexes. Initial possibilities considered were neurotransmitter disorders or structural midbrain lesions. Video-electroencephalography showed excessive ocular muscle activity with no epileptiform EEG correlates. Neuroimaging and neurometabolic workup including tandem mass spectrometry, urine gas chromatography mass spectrometry were normal. The neurotransmitter levels in the CSF, serum, and urine were not done. Clinical exome sequencing revealed a novel pathogenic homozygous variation in exon 14 [c.1196A>C (p.Asp399Ala)] of the SLC18A2 gene confirming the diagnosis of infantile Parkinsonism-dystonia-2. The same variation was detected in the heterozygous condition in both the asymptomatic parents. This variant was not reported in the 1,000 genome database. Treatment with L-dopa failed and hence later was started on pramipexole, clonazepam, and trihexyphenidyl with moderate clinical benefit.[1] Currently at the age of 2 years, the child is slowly gaining developmental milestones. She can walk with support, has a mature grasp, and speak 3–5 words but does not play with peers.

The oculogyric crisis is a clinical phenomenon of sustained dystonic, conjugate, and typically upward deviation of the eyes lasting from seconds to hours, although downward or lateral deviations were described. Though not life-threatening, management of oculogyric crises in the majority of inherited disorders is rather challenging.[1,2] These non-epileptic phenomena can be easily distinguished from epileptic seizures and paroxysmal tonic upgaze of infancy by means of history, thorough clinical examination, and electroencephalography.[3] They occur because of the midbrain and putaminal lesions, impairment of interstitial nucleus of Cajal, disorders affecting dopamine synthesis, and transport especially aromatic L-amino acid decarboxylase (AADC) deficiency, sepiapterin reductase deficiency, and dopamine transportopathies (infantile parkinsonism-dystonia-1 and 2).[3,4] Besides, the oculogyric crisis was also described in various hereditary movement disorders such as Kufor Rakeb disease, Pantothenate kinase-associated neurodegeneration, Hypomyelination with atrophy of basal ganglia, and cerebellum syndrome, ataxia-telangiectasia and Wilson disease.[4] The response to L-dopa is one of the criteria to differentiate Sepiapterin deficiency and AADC deficiency. The oculogyric crisis improves with L-dopa in the former, whereas it will not respond in the latter. Besides, AADC deficiency usually responds to pyridoxine and gradually worsens by evening.[5] However, in the case of vesicular monoamine transporter 2 (VMAT2) deficiency, L-dopa may worsen the problem. The pathophysiology is believed to be because of a deficit in central dopamine transmission resulting in overactive striatal acetylcholine release. In structural lesions (basal ganglia and midbrain), these crises occur because of the disruption of the nigrostriatal pathway.[6]

Infantile Parkinsonism-dystonia-1 is caused by mutations in SLC6A3 gene encoding DAT1 (dopamine transporter) in the presynaptic neurons. Infantile Parkinsonism-dystonia-2 (Brain serotonin-dopamine deficiency) is caused by mutations in the SLC18A2 gene encoding VMAT2.[5,6] VMAT2 plays a key role in the translocation of dopamine and serotonin into synaptic vesicles and is necessary for mood stability, motor control, and autonomic function. The VMAT2 deficiency leads to defective synaptic loading of monoamines which leads to impaired neurotransmission and symptoms related to the depletion of monoamines. The disorder usually starts with Parkinsonian features such as hypomimia, hypokinesis, tremor, and gradually the infant may develop oculogyric crisis, ptosis, myoclonic epilepsy, dementia, and autonomic dysfunction such as abnormal sweating, poor sleep, and cold extremities.[5,6,7] Brain imaging can be normal. However, the increased levels of neurotransmitter metabolites, namely homovanillic acid and 5-hydroxy indole acetic acid as well as decreased levels of norepinephrine and dopamine, especially in the urine help us in the diagnosis.[8] The summary of previously reported cases of infantile Parkinsonism dystonia-2 in the literature has been depicted in Table 1. Management includes administration of anticholinergics such as benztropine in acute cases. If no response, then a combination of oral benzodiazepines such as clonazepam and dopamine agonists might provide symptom relief.[7,8]

Table 1.

Summary of clinical, laboratory features, genetic variants and outcomes of the children with infantile parkinsonism-dystonia-2

Study	No. of patients	History of consanguinity	Age at first presentation	Presenting complaints	Neurotransmitter levels	L-dopa trial	Management	Genetic variant	Outcome
Rilstone et al.[5]	8	Yes	4 months	Hypotonia, Loss of acquired head control, oculogyric crises	CSF: 5-HIAA, HVA-N; Urine: elevated 5-HIAA, HVA Decreased NE, D	Ineffective, worsened	Pramipexole	c. 1160C>T p.(Pro387Leu)	Drastic improvement of dystonia within a week of therapy
Jacobsen et al.[6]	2	Yes	6 weeks	Hypotonia, poor head control, myopathic facies	CSF: mildly elevated 5-HIAA, normal pterins and HVA; low blood serotonin	Ineffective, worsened	Pramipexole	c. 710C>A p.(Pro237His)	Younger sibling died at 10 years due to respiratory failure. Dystonia improved in elder sibling
Rath et al.[7]	2	Yes	4 months	Hypotonia, oculogyric crises	CSF: 5-HIAA, HVA-N; low blood serotonin; Urine: elevated 5-HIAA, HVA	NA	Pramipexole	c. 710C>A p.(Pro237His)	Younger sibling died at 3 years from multiple organ failure. Improvement of dystonia within two months of therapy
Padmakumar et al.[8]	1	Yes	NA	Motor delay, limb dystonia, oculogyric crises	CSF: 5-HIAA, HVA-N	Ineffective	NA	c. 946C>G p.(Pro316ALA)	Died at 5.5 years due to respiratory failure
Present case	1	No	4 months	Hypotonia, global developmental delay, oculogyric crises	NA	Ineffective	Pramipexole, trihexyphenidyl, clonazepam	c. 1196A>C p.(Asp399Ala)	Moderate improvement in dystonia. Slow gain of milestones.

NA - Not available; CSF - Cerebrospinal fluid; 5-HIAA - 5-hydroxyindole acetic acid; HVA - Homovanillic acid; N - Normal; NE - Norepinephrine; D - Dopamine

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