Levodopa Responsive Dystonia Parkinsonism, Intellectual Disability, and Optic Atrophy Due to a Heterozygous Missense Variant in AFG3L2.

AFG3L2 mutations are associated with several neurodegenerative disorders. , , , , 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. AFG3L2 subunits form homo‐oligomeric complexes or hetero‐oligomeric complexes with paraplegin, located in the mitochondrial inner membrane, essential for protein quality control.

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.

Case Report

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).

Video 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. The variant was absent from the gnomAD database and classified as pathogenic (ACMG with modifications; PP1_strong, PM2, PS4_supporting, PM1_supporting, PP3).

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.

FIG. 1

Family pedigree. Black symptoms indicate individuals with the AFG3L2 missense variant c.1064C>T; p.(Thr355Met). Arrow indicates proband. *indicates presence of dystonia. ^indicates presence of sensorineural hearing loss, complex ophthalmoplegia and spastic ataxia. +indicates presence of dysarthria, ataxia and sensorineural hearing loss.

TABLE 1

Clinical details of family members carrying the AFG3L2 variant

Pedigree number	Sex	Age (years)	Optic atrophy	Cognition	Additional manifestations
II‐2	Female	39	Yes	Learning disability	Sensorineural hearing loss Dysarthric speech (cerebellar) Gait ataxia (cerebellar)
II‐4	Male	41	Yes	Learning difficulties	Sensorineural hearing loss Complex ophthalmoplegia Spastic ataxia Right ankle deformity
III‐2	Male	17	Yes	Mild intellectual disability	Nil
III‐3	Male	13	Yes	Moderate intellectual disability	Dopa responsive dystonia Parkinsonism
III‐4	Male	12	Yes	Moderate intellectual disability	Dopa responsive dystonia
III‐6	Male	7	Yes	Global developmental delay	Nil
III‐7	Female	5	Pending review	Pending review	Mild dystonia
III‐8	Male	13	Yes	Moderate intellectual disability	Nil

Video 2

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

Discussion

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). , , , , 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. , 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. 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.

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. 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. 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. Secondly, Magri et al 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 al 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. 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.

Author Roles

Research project: A. Conception, B. Organization, C. Execution

Manuscript preparation: A Writing of the first draft, B. Review and Critique

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.

Disclosures

Ethical Compliance Statement

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.

Funding Sources and Conflicts of Interest

No specific funding was received for this work and the authors declare that there are no conflicts of interest relevant to this work.

Financial Disclosures for Previous 12 Months

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

Click here for additional data file.