AFG3L2 mutations are associated with several neurodegenerative disorders.1-5 The ATP-dependent mitochondrial AAA+ metalloprotease (m-AAA) has 2 subunits: AFG3L2 and paraplegin. AFG3L2 is encoded by the gene AFG3L2 and paraplegin is encoded by the gene, SPG7.6 AFG3L2 subunits form homo-oligomeric complexes or hetero-oligomeric complexes with paraplegin, located in the mitochondrial inner membrane, essential for protein quality control.6 We report the first family with AFG3L2-related autosomal dominant optic atrophy (DOA) and intellectual disability with two members having the additional manifestation of dopamine responsive dystonia parkinsonism. The proband is a 13-year-old boy with optic atrophy and moderate intellectual disability diagnosed at 5-years of age. At 7.5-years of age, he presented with progressive limb dystonia, where symptoms worsened towards the end of the day when he would require assistance for mobilizing. He walked at an appropriate age, though always with in-toeing and intermittent toe-walking. At 7.5 years of age, examination showed dystonic lower limb posturing at rest, a dystonic gait with foot inversion, toe walking, arm flexion, and loss of arm swing, and parkinsonian features of paucity of facial expression, bradykinesia, shuffling when turning and postural instability (Video 1, segment 1). Segment 1 demonstrates the dystonia and mild parkinsonism of III-3 at 7.5-years-old. There is gait dystonia, bradykinesia, shuffling when turning and asymmetric dystonic posturing of his upper limbs. Segment 2 shows III-3 on 4 mg/kg/day of levodopa. There is significant improvement in the gait but with some subtle arm posturing and left foot inversion still present whilst running with his unaffected sibling, Segment 3 shows III-3 at 13-years-old with more prominent parkinsonism. He has a bradykinetic, stooped gait. Segment 4 shows subtle gait dystonia with bilateral feet inversion and reduced right arm swing and subtle posturing in III-4 prior to levodopa. Video content can be viewed at https://onlinelibrary.wiley.com/doi/10.1002/mdc3.13538 MRI head showed isolated hypoplastic optic nerves. Cerebrospinal fluid analysis revealed low biopterin 14.96 nmol/L (25.00–45.00), homovanillic acid 0.259 μmol/L (0.345–0.716) and HVA:5-HIAA ratio 1.46 (2.30–4.00) with normal protein, glucose, lactate, and amino acids. These findings were consistent with a potential diagnosis of GTP cyclohydrolase deficiency, which was not supported by genetic analysis as outlined below. Serum alpha-fetoprotein, copper, caeruloplasmin, uric acid and thyroid function testing and urine metabolic screen were normal. Chromosome microarray was normal. Next generation sequencing in 2016 using a 130-gene movement disorder panel (TruSight One panel [FC-141-1007] on an Illumina NextSeq550) did not identify any pathogenic or likely pathogenic variants, including full coverage of all known disorders of monoamine metabolism. Levodopa trial at 4 mg/kg/day resulted in significant, but incomplete improvement in dystonia (Video 1, segment 2) enabling maintenance of independent ambulation throughout the day. However, his dystonia gradually worsened with escalating levodopa requirements. At recent review at 13-year-old on levodopa 12.5 mg/kg/day, the patient had more prominent parkinsonism with a stooped posture and difficulty initiating movements (Video 1, segment 3). Whole genome sequencing conducted as part of Economic and Psychosocial Impacts of Caring for Families Affected by Intellectual Disability study, ethics reference no: HREC/16/HNE/309, identified a heterozygous pathogenic missense variant in AFG3L2 (NM_006796.2:c.1064C>T; p.(Thr355Met)), previously reported in a family with DOA and hyperkinetic movements, ataxia and dystonia.1 The variant was absent from the gnomAD database and classified as pathogenic (ACMG with modifications; PP1_strong, PM2, PS4_supporting, PM1_supporting, PP3).7 Several family members had optic atrophy and variable intellectual disability (Fig. 1): proband (III-3), mother (II-2), three brothers (III-2, III-4, III-6), maternal cousin (III-8) and maternal uncle (II-4). Dystonia emerged in III-4 at 11-years of age (Video 1, segment 4), partially responsive to 3 mg/kg/day levodopa. III-7 had mild limb dystonia when running at 5-years of age but no optic atrophy or intellectual disability and remains under review. II-2 and II-4 had sensorineural hearing loss and ataxia with ophthalmoplegia only seen in II-4. The AFG3L2 variant segregated to affected family members and was absent in II-1, III-1, III-5 and III-9 (Fig. 1). Clinical details of individuals with the AFG3L2 variant are shown in Table 1 and Video 2. Sensorineural hearing loss Dysarthric speech (cerebellar) Gait ataxia (cerebellar) Sensorineural hearing loss Complex ophthalmoplegia Spastic ataxia Right ankle deformity Dopa responsive dystonia Parkinsonism Full video from the 2021 Video Challenge discussion of this case. Video content can be viewed at https://onlinelibrary.wiley.com/doi/10.1002/mdc3.13538 Previously, heterozygous variants in AFG3L2 were described in DOA and autosomal dominant spinocerebellar atrophy type 28 (SCA28), while homozygous or compound heterozygous variants were described in distinct neurodegenerative disorders, including spastic ataxia type 5 (SPAX5).1-5 SCA28 manifests as adult-onset, slowly progressive cerebellar ataxia and SPAX5 has a severe phenotype of early-onset spasticity, cerebellar ataxia, oculomotor apraxia and progressive myoclonic epilepsy with basal ganglia and cerebellar abnormalities on brain MRI.2, 5 DOA associated with AFG3L2 variants was described in 12 families, with some individuals exhibiting additional phenotypic features of intellectual disability, sensorineural deafness, spasticity, cerebellar signs, dystonia, myoclonus or chorea.1 This included an individual with the same mutation as this report (p.T355M) and an overlapping phenotype but no details on levodopa response. AFG3L2 interacts with OPA1, which encodes a mitochondrial GTPase responsible for the fusion of the inner mitochondrial membrane, and disease-causing variants in OPA1 are responsible for 75% of cases of autosomal dominant DOA.8 Many monogenic disorders of dopamine biosynthesis, such as GTP cyclohydrolase 1 deficiency remain stable in severity and levodopa response, while levodopa responsiveness can also be noted in otherwise progressive disorders, like some cases of ataxia telangiectasia and neuronal intranuclear inclusion disease.9 Progressive dystonia has been reported in AFG3L2-related disorders, but levodopa responsive dystonia had not been previously reported. However, a 25-year-old female with heterozygous variants in both AFG3L2 and SPG7 (AFG3L2:p.R468C and SPG7:p.Glu127SerfsTer2) was described with progressive manifestations of optic atrophy, cognitive impairment, spastic ataxia and levodopa responsive parkinsonism.10 The AFG3L2 variant in this individual had been reported in DOA with mild intellectual disability suggesting concurrent AFG3L2 and paraplegin defects likely cause a distinct defect resulting in a complex, neurodegenerative phenotype. Our proband did not have variants in SPG7 or OPA1. It has not been explicitly described how dysfunction of the AFG3L2 subunit results in altered neurotransmitter levels in the central nervous system and dopamine responsiveness of the subsequent movement disorder. We postulate that this effect may be mediated through two possible pathways. The first possible mechanism is by the dysregulation of Ca2+ homeostasis, as mitochondria play a crucial role in modulation of neuronal cell Ca2+ levels, which can result in altered neurotransmitter release.11 Secondly, Magri et al10 demonstrated abnormal dopaminergic uptake in the basal ganglia on single photon emission computed tomography (SPECT)/dopamine transporter (DaT) scan in their proband with concurrent AFG3L2 and SPG7 variants. Additionally, Baderna et al8 showed in functional studies that a variant in AFG3L2 close to the AAA domain of the protein (as in our family) resulted in destabilization of the long isoforms of OPA1 leading to mitochondrial fragmentation. Finally, variants in the OPA1 gene have been causative for genetic forms of Parkinson's disease with functional studies showing the mitochondrial dysfunction associated with this results in a significant loss of dopaminergic synapses.12 Whilst this is still postulation, the relationship between some AFG3L2 variants and OPA1 dysfunction may be a factor in the dopamine responsive nature demonstrated in our family. To our knowledge, our index case is the first described patient with AFG3L2-related, progressive levodopa responsive dystonia parkinsonism in a family with AFG3L2-related DOA, intellectual disability, and additional neurological manifestations. We propose that in addition to optic atrophy, dystonia, with or without parkinsonism, may be a prominent manifestation of AFG3L2-related disease and a trial of levodopa therapy is warranted. We wish to thank the family for allowing us to share their story. We would like to thank Dr Michael Buckley for his assistance with the genetic analysis. We would like to thank Dr Deborah Schofield for her role in the family's diagnosis as part of the Economic and Psychosocial Impacts of Caring for Families Affected by Intellectual Disability study. Open access publishing facilitated by The University of Sydney, as part of the Wiley - The University of Sydney agreement via the Council of Australian University Librarians. WW: 1A, 1B, 1C, 2A, 2B. CT: 1A, 1C, 2B. RCD: 1A, 2B. TR: 1C, 2B. MF: 1C, 2B. EP: 1C, 2B. EMM: 1C, 2B. KRK: 1B, 1C, 2B. SSM: 1A, 1B, 1C, 2B. The use of diagnostic and clinical information of patients in this study complied with the requirements of the clinical ethics committee of the Children's Hospital at Westmead. Verbal and written informed consent for use of information and videos was gained from the patients (when adult consent was possible) or the parents of the patients for those under the age of 14 years of age. All authors confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. No specific funding was received for this work and the authors declare that there are no conflicts of interest relevant to this work. SSM was supported by the Cerebral Palsy Alliance, Australia (award number PG01217). KRK receives salary from NSW Health, funding from the Paul Ainsworth Family Foundation, the Michael J. Fox Foundation Aligning Science Across Parkinson's (ASAP) initiative, and honorarium from Abbvie, Seqirus and Research Review Australia. Table S1 Characteristics of individuals reported with AFG3L2 variants with manifestations of dystonia or parkinsonism Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
GNAO1 (OMIM 139311) encodes a GαCNS protein responsible for regulation of GABA-B and α2-receptors, and neurotransmitter release. Mutations of GNAO1 are reported in patients with epileptic encephalopathy (EE) at times with a movement disorder (MD); some display severe hyperkinetic movements without EE, three underwent Deep Brain Stimulation (DBS) with reduction in exacerbations.1–4 (see online supplementary table 3, supporting information (SI)).
### Supplementary Material
Supplementary table 1[SP3.pdf]
We describe the MD phenomenology and course in three patients identified from neurology services in Brisbane and Glasgow with GNAO1 -related MD, highlighting effectiveness of DBS in exacerbations.
Informed consent was obtained. Four MD specialists reviewed videos (baseline, exacerbations, post-DBS) using a Proforma (SI) and reached a consensus on movement phenomenology.
All patients had global delay, central hypotonia and MD noted in early life (see online supplementary table 1, patient synopsis, SI). Patient 3 initially showed bradykinesia, rigidity and dystonia; patient 1 resting tremor. All had been diagnosed with dyskinetic Cerebral Palsy (CP), without substantive MRI findings. Medication for baseline MD had variable efficacy (see online supplementary table 2, SI). MRI demonstrated mild progressive atrophy over 6 years in two patients (see online supplementary figure 1, SI). MRI during an exacerbation revealed restricted diffusion in the internal capsules and splenium (corpus callosum) in one (figure 1).
### Supplementary Material
Supplementary figure 1[SP1.JPG]
Figure 1
Response to Deep Brain Stimulation (DBS) and MRI changes. PICU - Pediatric Intensive Care Unit.
Whole exome sequencing identified de novo heterozygous mutations in the GNAO1 gene in all three patients, confirmed with Sanger sequencing.
### MD phenomenology
Dominant baseline MD varied between patients; agreed features included …
N-methyl-D-aspartate receptor antibody-mediated encephalitis (NMDAR-AbE) is an increasingly recognised and treatable encephalitis, with a predilection for children and young adults.1 2 As earlier immunotherapy improves outcomes, timely and accurate recognition of NMDAR-AbE is a major clinical aim.2
The characteristic polysymptomatic presentation of NMDAR-AbE includes early neuropsychiatric deficits with seizures, autonomic disturbance, reduced consciousness and a movement disorder (MD).1 2 This MD, seen in around 90% of cases, can be the presenting feature, particularly in children,1 and is typically hyperkinetic with limb plus orofacial involvement.1–5 To date, elegant detailed descriptions exist in a few patients.4 However, small series have used highly variable phenomenological descriptions.1–5 Therefore, the phenomenology of the associated MD lacks consensus. Its clearer description will facilitate confident recognition and enable earlier immunotherapy administration in NMDAR-AbE.
Expert-rater descriptions remain the gold standard to define phenotypes in movement disorders. In this study, ratings from seven experts across 76 videos were used to better define the MD in NMDAR-AbE.
### Subjects
Autoimmune neurology researchers contributed 44 videos from 20 patients who met diagnostic criteria for NMDAR-AbE.e1 A PubMed search for ‘anti-NMDAR encephalitis’ and ‘NMDAR-antibody encephalitis’, plus associated references, revealed 32 videos from 14 subjects, in eight papers from 14 subjects.3 , e2–8 Clinical features, temporal progression, outcomes and investigation findings were collated from case note reviews by the researchers and from data in published papers. Twenty videos from 18 age-matched and sex-matched (age range 2–41 years, median 12, 50% female) disease controls were selected from the literature (online supplementary data).3 e9–19
### Supplementary data
[jnnp-2018-318584supp004.pdf]
### Movement disorder classification
Seven experts (KB, VF, AEL, TL, NN, KS and MT) established a consensus glossary of terms (online supplementary data, modified from Mohammed et al 3). Subsequently, each expert blindly and independently rated 76 videos from 34 patients with NMDAR-AbE (median two videos …
Abstract Background Variants in EIF2AK2 have been recently associated with a spectrum of neurological disease encompassing isolated dystonia to fever‐related neurological decompensation, movement disorders and leukodystrophy. Case A 32‐year old patient presented with childhood‐onset episodes of neurological decompensation after febrile illness, progressive anarthria, dystonia and spasticity. The T2/FLAIR MRI showed bilateral posterolateral putamen hyperintensities and white matter changes suggestive of leukodystrophy. Initial extensive metabolic workup and whole genome sequencing (WGS) was unremarkable. Re‐analysis of the WGS data revealed a variant in exon 3 of the EIF2AK2 gene [ (NM_001135651.3): c.92C > G (p.Pro31Arg)]. EIF2AK2 ‐associated disorders should be incorporated into the differential diagnosis of the syndrome of fever‐related neurological decompensation with movement disorders, especially in the presence of abnormal neuroimaging. Literature review Disease‐causing variants in EIF2AK2 have been reported in 24 individuals from 16 families in the literature to date. Two broad phenotypes have been described, including: (1) childhood‐onset generalized dystonia and a normal brain MRI; and (2) early childhood‐onset developmental delay combined with movement disorders, spasticity, and seizures in some. Notably, 92% of these patients have neurological deterioration after febrile illness or other physiological stress. Hypomyelination or delayed myelination and thin corpus callosum are seen in most patients and lower medullary lessions are common. Basal ganglia lesions have been reported previously in one case. Conclusions EIF2AK2 ‐associated disorders should be incorporated into the differential diagnosis of the syndrome of fever‐related neurological decompensation with movement disorders, especially in the presence of abnormal neuroimaging.
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