Expanding the Phenotype of DNM1L-Related Mitochondrial Cytopathy: A Case Series

Article information

Ann Child Neurol. 2025;33(4):198-201

Publication date (electronic) : 2025 September 26

doi : https://doi.org/10.26815/acn.2025.00871

Haleigh Stafford, MD, Naomi Kass, BA, Mered Parnes, MD, Mariam Hull, MD

Pediatric Movement Disorders Clinic, Section of Pediatric Neurology and Developmental Neuroscience, Texas Children's Hospital and Baylor College of Medicine, Houston, TX, USA

Corresponding author: Naomi Kass, BA Pediatric Movement Disorders Clinic, Section of Pediatric Neurology and Developmental Neuroscience, Texas Children's Hospital and Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA Tel: +1-713-498-3781 E-mail: Naomi.Kass@bcm.edu

Received 2025 March 18; Revised 2025 June 14; Accepted 2025 September 12.

Dynamin-1-like protein (DNM1L), also known as dynamin-related protein 1 (DRP1), is a guanosine triphosphatase (GTPase) that constitutes a key component of the mitochondrial fission machinery [1,2]. Dysregulation of DNM1L-dependent mitochondrial fission has been implicated in several neurodegenerative disorders, including Alzheimer’s disease, Huntington’s disease, and Parkinson’s disease; however, the phenotypic spectrum of de novo DNM1L mutations remains poorly understood [3-5]. Progressive encephalopathy, refractory epilepsy, and lethal status epilepticus have all been associated with de novo variants of DNM1L [6-8]. Nonetheless, milder phenotypes have also been documented, including ataxia, developmental delay, dystonia, muscular atrophy, and peripheral neuropathy [9,10]. In this report, we describe the clinical presentation of two patients with de novo DNM1L variants, with a particular focus on the movement disorders observed in each case. Their clinical courses and responses to treatment are also discussed.

Patient 1 is a right-handed female who first presented at age 7 with delayed gross motor development and involuntary movements. She was born at 40 weeks of gestation via spontaneous vaginal delivery. Her early growth and development were normal until approximately 9 months of age, when it was noted that she was unable to sit independently. She subsequently achieved sitting at 11 months and walking at 18 months. By age 2, she experienced gross motor regression, losing the ability to walk. At that time, an action tremor of the hands and a head tremor were first observed. She also underwent surgery for strabismus. Between ages 3 and 4, she developed stiffness of the extremities without posturing, more pronounced in the bilateral lower limbs. By age 5, she required a wheelchair because of leg and truncal weakness. Her past medical history was notable for asthma, and her family history included an action tremor in her father, paternal aunt, paternal uncle, and paternal grandfather.

At age 7, she was found to have nystagmus and poor saccades, and by age 9 she had limited extraocular movements in all directions, particularly horizontally. This progressed to chronic progressive external ophthalmoplegia (CPEO), a marker of mitochondrial disease. There was no evidence of optic atrophy or pigmentary retinopathy. Strength was decreased in all extremities, with spasticity, bilateral ankle clonus, and extensor plantar responses. She also exhibited significant axial hypotonia and dysarthria, along with an action tremor of the hands, a small-amplitude lateral oscillatory head tremor, and mild finger chorea (Supplementary Video 1). Hearing was normal. Laboratory testing revealed a 46, XX karyotype and normal plasma amino acids, very long-chain fatty acids, and urine organic acids. Cerebrospinal fluid analysis of neurotransmitters was unrevealing. Magnetic resonance imaging (MRI) demonstrated bilateral thalamic hyperintensities on the T1 axial view without additional abnormalities (Fig. 1A). Magnetic resonance spectroscopy was normal, and electromyography and nerve conduction studies (EMG/NCS) revealed possible axonal sensory and motor neuropathy. Ultimately, trio whole exome sequencing (WES) revealed compound heterozygosity for de novo pathogenic variants in DNM1L (c.763_764dup and c.1778T>C). The pathogenic de novo DNM1L variants were considered most likely to account for her phenotype, as other potentially significant variants were inherited.

Fig. 1.

Magnetic resonance imaging (MRI) of two patients presenting with gross motor delay, tremor, and dystonia, both found to have de novo variants in dynamin-1-like protein (DNM1L). (A) Brain MRI of Patient 1 revealing bilateral thalamic hyperintensities on the T1 axial view. (B) Brain MRI of Patient 2 with normal findings and no clear thalamic hyperintensities.

Propranolol was initiated for the action tremor but was discontinued because of limited benefit. Carbidopa-levodopa therapy was then started, resulting in marked improvement in stiffness, tremor, and sialorrhea. She developed mild peak-dose levodopa-induced dyskinesia, which subsequently improved. After three weeks of treatment, she was able to ambulate with a walker.

She experienced two episodes of developmental regression. The first occurred during an inpatient admission for pneumonia at age 8, and the second at age 11 during hospitalization for progressive weakness with refusal to eat or drink. She developed gastroparesis requiring G-tube placement. Between these two episodes, she was diagnosed with attention-deficit/hyperactivity disorder at age 9. At age 12, she underwent bilateral Achilles tendon recession, left tibial osteotomy, left calcaneal osteotomy, and bilateral flexor toe tenotomy. Additional orthopedic issues included scoliosis. She remains on carbidopa-levodopa; however, increased ‘off’ times have necessitated gradual escalation in dose and frequency. Over the past several years, her gait has worsened, and she now requires a wheelchair for ambulation over even short distances. She has also developed worsening dysarthria, with only about 50% of speech intelligible.

Patient 2 is a right-handed male who first presented at age 2 with gross motor delay and involuntary movements. His birth history was unremarkable, and he was healthy until a febrile illness at approximately 3 months of age, after which he experienced gross motor regression and lost the ability to roll over, a milestone he had previously achieved. He later began crawling at 12 months, standing at 18 months, and walking at 20 months. His parents noted that he appeared ‘off balance’ while walking, and he subsequently developed an action tremor of the upper extremities. His past medical and surgical history were otherwise unremarkable, and there was no known family history of neurological disorders.

At age 8, physical examination demonstrated full extraocular movements and dysarthric speech, with normal strength. He exhibited an irregular action tremor of the distal upper extremities, brisk reflexes, and clonus at the right patella. Generalized dystonia was present, more pronounced on the left hemibody, with equinovalgus posturing of the left foot, leftward truncal flexion, and bilateral elbow flexion with shoulder extension (Supplementary Video 2). This posturing improved slightly when walking backward. Laboratory studies and brain MRI revealed no significant abnormalities (Fig. 1B). EMG/NCS were normal, and alpha-fetoprotein levels were within normal limits, excluding ataxia telangiectasia. Trio WES identified heterozygosity for a de novo pathogenic variant in DNM1L (c.1986_1988del).

Baclofen and clonidine were trialed without benefit. The patient was subsequently started on carbidopa-levodopa, which led to significant improvement in generalized dystonia and gait. However, impairing peak-dose dyskinesia emerged and did not improve over time. After several years of treatment, he developed more frequent ‘off’ periods accompanied by painful toe flexion dystonia and progressive bilateral inward foot rotation, with moderate improvement following the addition of pramipexole. He also received onabotulinum neurotoxin A injections to the toe flexors, but with limited effect. During febrile illnesses, his parents reported worsening of the arm tremor along with notable muscle weakness and fatigue. Over time, his handwriting ability has progressively declined, and he has developed anxiety, which is currently being managed with propranolol and fluoxetine.

Both patients presented with gross motor delay, tremor, ataxia, chorea, and dystonia (Table 1). In addition, both experienced motor regression in the context of febrile illness. These cases further broaden the phenotypic spectrum of DNM1L-related mitochondrial cytopathy. Both demonstrated marked improvement in gait following initiation of carbidopa-levodopa, along with partial improvement in other symptoms. However, both developed peak-dose dyskinesia, which improved over time in the first patient but remained impairing and dose-limiting in the second. The clinical response to dopamine supplementation suggests an underlying dopamine deficiency state, potentially presynaptic or partially postsynaptic, although further research is necessary to elucidate the underlying mechanism.

Table 1.

Key aspects of the history and clinical course of both patients included in this report

No International Review Board was required for preparation of this case series; ethical guidelines were followed to assure patient privacy was maintained. Written consent from patient guardians was obtained before obtaining videos for purposes of education within a medical peer reviewed journal.