A female patient presented to pediatric services with cognitive and behavioral difficulties. Parents were of Sephardic Jewish extraction and consanguineous (third-degree cousins). Pregnancy and childbirth were normal, and she attained normal neurodevelopmental milestones during the first year of life. She walked at 13 months. At age 3 years, she developed social and communication difficulties and speech regression. At 4.5 years, gait became unsteady with frequent falls. Motor regression continued in childhood, with progressive generalized dystonia (truncal predominance; see Video, Sequence 1), associated with lower-limb spasticity leading to loss of ambulation at age 9 (see Video, Sequence 2), and loss of independent sitting by age 15 (see Video, Sequence 3). Bilateral spontaneous and intentional upper-limb myoclonus and postural and intentional tremor developed (See Video, Sequences 2 and 3). Oculogyric crises and ocular dysmetria were noted, without ophthalmological evidence of optic atrophy. Atypical absence seizures were evident from age 8. Cognition, measured at age 7 with Wechsler's Abbreviated Scale of Intelligence, was globally below average, with dissociation of verbal and performance domains. Cognitive dysfunction was progressive over time. Intrathecal baclofen therapy was administered for symptomatic control of generalized spasticity, but the progressive nature of her disease and development of skeletal deformities limited functional outcome.
At age 15, she developed a severe status dystonicus (see Video, Sequence 4). For 2 months before the occurrence of the status dystonicus episode, the parents had noted progressive and accelerated worsening of dystonia of axial predominance. At the time, the child's treatment comprised intrathecal baclofen, clonazepam, and tetrabenazine. Deep brain stimulation (DBS), which had previously been discussed and rejected because of prominent pyramidal features, associated cerebellar symptoms, and the milder nature of her dystonia in earlier stages of the disease process, was now reconsidered. The palliative nature of DBS in a progressive disorder was explicitly explained to the child's parents, who consented to the procedure. Investigations before surgery were scheduled, but the child worsened further and presented multiple daily episodes of intense dystonic spasms, hyperthermia, and diaphoresis, without improvement following increasing pharmacolgical treatment. The child was admitted first to the Department of Pediatric Neurosurgery, followed 2 days later by a transfer to the intensive care unit (ICU). In relation with the severe dystonic crises, she presented with rhabdomyolisis and aspiration pneumonia. She was intubated and ventilated and under continuous intraveneous infusion of midazolam (0.2 mg/kg/hour) and sufentanil (0.2 gamma/kg/hour). Attempts to wean sedation on day 9 ended with a recurrent relapse into status dystonicus. Bilateral implantation of internal globus pallidus (GPi) and ventral intermediate thalamic (Vim) nuclei was performed in our center 16 days after the onset of dystonic storm, and GPi DBS was initiated 1 day later. Suspension of sedation and extubation were possible 10 days after DBS debut. The total stay of the child in the ICU was 4 weeks. At 9-month follow-up, she had experienced no further episodes of status dystonicus. Oculogyric crises resolved almost completely. Furthermore, there was an unexpected significant improvement in her upper-limb postural and intentional tremor, with functional improvement noted in her ability for holding objects and feeding (see Video, Sequences 5 and 6).
Detailed screening of blood, urine, and cerebrospinal fluid for neurometabolic causes was negative. No mutations were identified in either PANK2 or APTX.
On EEG, background activity was moderately slow with superimposed bursts of spike and slow waves more prominent anteriorly. At age 11, a delay in visual evoked potentials was documented. Serial electromyograms at ages 9 and 11 did not demonstrate signs of denervation, and nerve conduction studies showed no distal axonal-type sensorimotor neuropathy.
Investigations revealed a homozygous missense amino acid substitution (c.1640A>G, E547G; Fig. 1). The mutation showed appropriate familial segregation, and both parents were heterozygotes. The E547G missense substitution was not detected in >400 control chromosomes. Further analysis of this missense change using PolyPhen (http://genetics.bwh.harvard.edu/pph/) was undertaken to predict the functional effect of this amino acid substitution, revealing a PSIC score of 1.967.
Brain MRI was undertaken at age 8, 10, 11, and 15 years. Nonprogressive subtle cerebellar atrophy was evident (Fig. 2A, B, and F). Serial MRIs showed increasing accumulation of iron in the globus pallidus (GP) and substantia nigra (SN) (Fig. 2C–E) and slightly reduced volumes of the optic nerves and chiasm.
The clinical picture of progressively worsening dystonia, severe spasticity, cerebellar signs, and cognitive dysfunction, together with mild cerebellar atrophy and hyposignal in T2-weighted MRI image in the GP and SN, pointed toward an atypical neuroaxonal dystrophy (NAD), a subgroup of PLA2G6-associated neurodegeneration (PLAN). PLAN comprises a continuum of heterogeneous autosomal recessive neurodegenerative disorders,[1, 2] including disorders with disease onset in infancy (classical infantile neuroaxonal dystrophy; INAD), MIM256600[1, 3, 4] childhood (atypical neuroaxonal dystrophy, atypical NAD, including Karak syndrome MIM610217), and adulthood (early-onset dystonia-parkinsonism MIM612953).To date, approximately 75 germline PLA2G6 mutations have been identified. Infantile presentation accounts for 80% to 85% of cases, whereas atypical childhood presentations have only rarely been described.
The final diagnosis is atypical NAD, associated with a novel PLA2G6 mutation presenting initially with a neuropsychiatric phenotype. In this type of PLAN, clinical presentation is later in childhood (mean age: 4.4 years), compared to classical INAD (mean age: 1.3 years), and has only rarely been reported. In atypical NAD, neurobehavioral features are common and somewhat reminiscent of those observed in other NBIA phenotypes, including adult-onset PLAN, pantothenate kinase-associated neurodegeneration (PKAN), and the newly described beta propeller-associated neurodegeneration. Our case also confirms the previously reported phenotypic overlap of atypical NAD with INAD (psychomotor regression, speech difficulties, pyramidal tract features, dystonia, and cerebellar signs), although other clinical features of INAD are less frequent (optic atrophy, truncal hypotonia, strabismus, fast rhythms on EEG, and prominent cerebellar atrophy on MRI).
The mutation described in this patient (E547G) appeared in the same region of the PLA2G6 protein domain where other PLAN mutations are described (R538S, R538C, K545T, K545E, E567K, and V582L). Although the majority of these mutations have been described in INAD, our patient's mutation and the previously reported mutation, V582L, have been demonstrated in patients with atypical NAD. The factors that determine the clinical phenotype and age of presentation of PLAN are still largely unknown, although there are some genotype-phenotype observations where (1) all individuals with two null alleles of PLA2G6 have INAD, (2) the less-severe atypical NAD phenotype is caused exclusively by missense mutations (as in our patient), and (3) common mutations associated with INAD impair the catalytic activity of the PLA2G6 protein, whereas three mutations associated with adult-onset PLA2G6-related dystonia-parkinsonism did not affect this function. Different PLAN phenotypes may indeed be caused by different mutations affecting the same amino acid residue. It is possible that different missense amino acid substitutions may differentially affect disruption of protein structure, and this may, in turn, determine clinical presentation. However it is also possible that additional genetic or environmental factors may play a role in determining age of disease onset and severity of symptoms in the PLAN disease spectrum.
We describe a case of atypical PLA2G6-associated neurodegeneration successfully treated with DBS after development of severe dystonic crises. Dystonic storm represents an acute worsening of chronic generalized dystonia, most frequently in secondary dystonia, with significant morbidity and mortality despite best medical management. A recent publication reported on 27 original cases presenting with dystonic storm episodes during evolution of generalized dystonia and an overview of the previously reported cases in the literature. Importantly, DBS allowed resolution of dystonic storm episodes in 33.7% of the patients versus only 10.1% of the episodes after first-line pharmacological treatment. DBS efficacy has been only exceptionally reported in NBIA patients who developed dystonic storm. Grandas and collaborators reported on a case of PKAN) related to PANK2 gene mutation in whom GPi DBS allowed the resolution of the dystonic storm episode early, within days, as in our patient.
The case we present illustrates the salient features of atypical PLAN and, additionally, highlights the novel use of DBS for symptomatic control of the severe dystonia encountered in this condition. To our knowledge, this is the very first case reporting of a PLAN patient who received GPi and Vim DBS for treatment of life-threatening dystonia. In this patient, the two targets have been implanted with the aim to improve dystonia and tremor by interfering with disrupted pallidal-thalamic-cortical and cerebellar-thalamic-cortical pathways. Interestingly, early during the administration of GPi DBS, symptoms of both dystonia and postural and intention tremor improved, as did myoclonus and oculogyric crises.
The phenotype of PLAN is expanding. The insidious onset, with social and communications difficulties as well as behavioral difficulties encountered in atypical PLAN, may lead to delayed diagnosis of such cases. Indeed, atypical PLAN may be more frequent than previously expected. Our case highlights the importance of neurological follow-up in children with neurobehavioral features to monitor closely for the evolution of neurological signs, which should prompt further investigation, including repeat neuroimaging studies. Our study also highlights that even in neurodegenerative disorders such as PLAN, although therapeutic strategies remain limited, DBS could be considered as a treatment option to alleviate symptoms of dystonia and improve functional abilities.
(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.
L.C.: 1A, 1B, 1C, 3A
M.A.K.: 1A, 1B, 1C, 3A
V.G.: 1B, 3B
S.G.-P.: 1C, 3B
T.R.: 1C, 3C
P.G.: 1C, 3B
A.M.M.d.R.: 1C, 3B
A.C.: 1B, 3B
L.M.: 1C, 3B
P.C.: 1B, 3B
The authors thank David Grabli, MD, PhD (Pôle des maladies du système nerveux, Fédération de Neurologie, Inserm-UPMC UMRS 975-CRICM, CNRS UMR 7225, groupe hospitalier Pitié-Salpêtrière, AP-HP, Paris, France; firstname.lastname@example.org), Eamonn Maher, MD, PhD (West Midlands Region Genetics Service, Birmingham Women's Hospital, Edgbaston, UK; email@example.com), Marlène Rio, MD, PhD, and Arnold Munnich, MD, PhD, (Département de Génétique, Hôpital Necker-Enfants-Malades, INSERM U781, Université Paris V, René Descartes, Paris, France; firstname.lastname@example.org;email@example.com) for case discussion, Neil Morgan, MD, PhD (Wellchild Pediatric Research Center and Department of Medical and Molecular Genetics, University of Birmingham College of Medical and Dental Sciences, Edgbaston, Birmingham, UK; firstname.lastname@example.org) for data on the frequency of this mutation (E547G) in control chromosomes, Fiona MacDonald, MD, PhD, (School of Clinical and Experimental Medicine, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham, UK; email@example.com) for undertaking diagnostic screening of PLA2G6, and Katharine Foster, MD, PhD (Department of Neuroradiology, Birmingham Children's Hospital, Birmingham, UK; firstname.lastname@example.org) for reviewing the neuroradiology.
Funding Sources and Conflicts of Interest: The authors report no sources of funding and no conflicts of interest.
Financial Disclosures for previous 12 months: Drs. Cif, Gonzalez, and Coubes have received lecture fees from Medtronic Company. Dr. Kurian has been funded by Action Medical Research (RTF1301) and by the Wellcome Trust and had received research support from BCH Research Foundation (grant nos.: BCHRF132F, DLAG RCTL13426, DLAG RCPF14653, and DLAG RCPF15131) and BDFNewLife (grant ref.: 07-08/09). Dr. Cif had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.