α‐Methylacyl‐CoA Racemase Deficiency in a Patient with Ataxia, Spasticity, and Segmental Dystonia
2024-08-12

Peroxisomal enzyme deficiencies are disorders caused by the lack or malfunction of one of the 60 known peroxisomal enzymes and manifest with diverse clinical signs.1 α-Methylacyl-CoA racemase (AMACR) deficiency is a rare, autosomal recessive disorder within this group2 characterized by elevated levels of C27-bile acid intermediates, pristanic acid, and mild elevation of phytanic acid. The disorder can manifest either in adulthood or the neonatal period. The clinical spectrum varies from hepatic changes and vitamin K deficiency in the neonatal and childhood period3 to neurologic manifestations in adulthood. The reported neurological features include relapsing encephalopathies, seizures, cerebellar signs, and tremor.2-4 Retinopathy has also been frequently reported in these patients.5 Nevertheless, the exact clinical spectrum remains unknown because of the rarity of this disorder. Here, we report a patient with AMACR deficiency and unique neurological features, which can add to the existing clinical spectrum of this disorder. A 56-year-old female was referred to the clinic because of imbalance and gait ataxia. Her symptoms began at the age of 27 years with hand tremor and coordination difficulties. By 35 years of age, she had difficulties gripping a ball, and at 40 years old, she developed gait imbalance. These symptoms progressively worsened, leading to illegible handwriting, things slipping from her hand, and concentration problems. At 48 years old, she experienced involuntary head movements and dysarthria. She was born from non-consanguineous Caucasian parents; in the family history, her mother had an unsteady gait in old age. The past medical history was negative except for hypertension treated with ramipril 5 mg daily. At the time of presentation to our clinic, she could not perform everyday activities because of fear of falling and complained of dysphagia. Neurological examination (Video 1) revealed saccadic pursuit in all directions, dysarthria, and laryngeal dystonia with voice tremor. She had mild cervical dystonia and a "no-no"-tremor of the head. Her gait was spastic-ataxic, and she was unable to perform tandem gait. Neuropsychological examination revealed cognitive impairment with a Montreal Cognitive Assessment score of 21of 30. The Scale for the Assessment and Rating of Ataxia score was 12.5 of 40, and the motor part of the Toronto Western Spasmodic Torticollis Rating Scale was 15 of 35. The patient's brain magnetic resonance imaging (MRI) revealed bilateral white matter hyperintensities in the thalami, internal capsule, and temporal regions (Fig. 1). Electromyography and neurography were normal. Electroencephalography showed subclinical rhythmic electrographic discharges of adults without typical epileptic spikes. Motor evoked potentials revealed increased central nerve conduction latencies to both arms. Visual-evoked potentials and tibialis somatosensory-evoked potential were unremarkable. Cerebrospinal fluid tests for oligoclonal bands, dementia markers, 14-3-3 protein, and borreliosis were all negative. Genetic analysis was negative for Fabry disease, frequent spinocerebellar ataxias, and Krabbe disease. The laboratory blood analysis showed increased neuron-specific enolase (38.5 μg/L, normal value [norm] <12.5), slightly increased phytanic acid (5.1 mg/L, norm <5), markedly increased pristanic acid (195.39 μmol/l, norm <2), and elevated total bile acids (17.4 μmol/L, norm <7.9). Exome sequencing revealed compound heterozygous missense variants in AMACR (ENST00000335606.11), including the pathogenic variant c.154T>C, p.Ser52Pro, and the previously unreported variant c.149A>G, p.Lys50Arg. Based on the genetic results and laboratory findings of increased pristanic and bile acid levels AMACR deficiency was diagnosed. AMACR deficiency is a very rare disease, with only 18 reported cases including 13 reported adult cases worldwide. The therapy involves reducing phytanic acid intake by restricting ruminant fats and dairy products. However, its effectiveness in AMACR patients is controversial.3 The reported patient could not tolerate the diet and, therefore, discontinued it. Because of the rareness of this disorder, the exact clinical spectrum is not yet fully understood. The clinical presentation and key features of previously reported adult cases are summarized in Table 1. The current case shares clinical and paraclinical manifestations with other adult AMACR deficiency cases, such as dysarthria, ataxia,6 tremor,4 elevated pristanic acid levels, and brain MRI changes with hyperintense signals in the thalami, pons, basal ganglia, and cerebral peduncles.4, 5 This case is nevertheless novel in terms of clinical manifestations, not only as it does not share some of the typical manifestations described in previous cases, such as seizures and encephalopathic episodes,1-9 but it also manifests with unique features such as cervical and laryngeal dystonia and dystonic tremor, thereby expanding the known AMACR deficiency disease spectrum. Seizures, dysarthria, short-term memory deficit, gait ataxia, sensorimotor polyneuropathy AMACR deficiency has to be considered in the differential diagnosis of cerebellar ataxia, particularly with seizures or recurrent encephalopathic episodes. Laboratory tests typically reveal increased pristanic acid and a decreased phytanic/pristanic acid ratio. Common other peroxisomal disorders associated with ataxia include adrenoleukodystrophy with increased very-long-chain fatty acids and Refsum disease with increased phytanic acid and an elevated phytanic/pristanic acid ratio.9 This case emphasizes the importance of considering AMACR deficiency in patients with undiagnosed cerebellar ataxia and seizure or atypical features, for example, dystonia, particularly when genetic testing for other conditions has been negative. Measuring serum phytanic and pristanic acid levels in patients with cerebellar ataxia and dystonia can lead to timely, accurate diagnosis, and appropriate management. Other differential diagnoses for ataxia with segmental dystonia (cervical, laryngeal) and dystonic head tremor include ataxia with vitamin e deficiency, spinocerebellar ataxia type 3, ataxia-telangiectasia, and TUBB4A-related disorders.10 (1) Research project: A. Conception, B. Organization, C. Execution; (2) Manuscript Preparation: A. Writing of the First Draft, B. Review and Critique. R.R.: 1B, 1C, 2A. M.G.: 1C, 2B. L.P.: 1C, 2B. M.B.: 1C, 2B. T.B.H.: 1C, 2B. S.Z.: 1A, 1B, 2B. Ethical Compliance Statement: We 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. Informed written patient consent was obtained. The authors confirm that the approval of an institutional review board was not required for this work. Funding Sources and Conflict of Interest: No specific funding was received for this work. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the previous 12 months: Ronak Rashedi and Lisa Prilop have no financial disclosures. Mathias Gelderblom received honoraria from Merz Pharma and AbbVie. Maxim Bester was a consultant for Acandis, Microvention, Tegus, Stryker, Cerenovus, Balt and phenox. Tobias Haack was supported by grants from the German Research Foundation. Simone Zittel received honoraria from Merz Pharma and was supported by grants from the German Research Foundation, the European Commission, the Damp Foundation and the Arbeitskreis Botulinumtoxin. We are greateful to the patient who agreed to the publication of the case report. Open Access funding enabled and organized by Projekt DEAL.