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Hereditary Spastic Paraplegia 7 Presenting as Multifocal Dystonia with Prominent Cranio‐Cervical Involvement

2021; Wiley; Volume: 8; Issue: 6 Linguagem: Inglês

10.1002/mdc3.13257

2330-1619

Marina Campins‐Romeu, Raquel Baviera‐Muñoz, Isabel Sastre‐Bataller, Luís Bataller, Teresa Jaijo, Irene Martínez‐Torres,

Neurological diseases and metabolism

Hereditary spastic paraplegias (HSP) are neurodegenerative disorders with significant clinical and genetic heterogeneity. To date, more than 80 causative loci of HSP have been identified, comprising autosomal dominant, autosomal recessive, X-linked and mitochondrial inheritance patterns.1 Spastic paraplegia type 7 (SPG7) is one of the most common autosomal recessive forms. SPG7 gene encodes paraplegin a mitochondrial metalloprotease involved in mitochondrial membrane trafficking, regulation of cell components and protein metabolism.2 SPG7 mutations have been widely referred as a frequent cause of mid-age onset hereditary cerebellar ataxia.3 Mitochondrial clinical features like optic neuropathy, progressive external ophthalmoplegia or parkinsonism are being increasingly recognized.4, 5 We report a SPG7 case presenting with multifocal dystonia with prominent cranio-cervical involvement. A 28-year-old Caucasian male with gait and speech problems was referred to our Movement Disorders clinic for further diagnostic and therapeutic assessments. He was born from healthy non-consanguineous parents. Family history was unremarkable and no relevant past medical history was reported. His neurological problems started at the age of 17 with clumsiness when playing football. One year later he suffered a quite sudden aphonia that 1 month later evolved to dysarthric speech and chewing difficulties without swallowing impairment. Cervical dystonia was especially triggered when speaking or chewing. At the age of 20, he developed clumsiness with manipulation and abnormal posturing of hands when writing. He did not recognize fluctuations throughout the day. Gait difficulties slowly worsened and at 31-years-old he was unable to run indefinitely. On initial examination oromandibular and cervical dystonia, mainly antero-caput, were prominent. He showed dystonic posturing and dystonic tremor in both hands. Dystonic postures in feet emerged when walking. Tandem gait was slightly unstable although he was able to perform it without aid. Deep-tendon reflexes were increased in lower limbs with no other pyramidal signs. Extraocular movements, smooth pursuit and saccades were normal. Levodopa trial for 4 months, tetrabenazine and trihexyphenidyl treatments reported no benefits. Botulinum toxin injections on sternocleidomastoids, digastric and genioglossus muscles achieved slight relief of speech, chewing and cervical dystonia. Acquired causes were extensively excluded. Serum copper, ceruloplasmin and 24-hour urinary copper were normal. Brain MRI demonstrated mild cerebellar atrophy and T2-weighted hyperintensities of the cerebral peduncles (Fig. 1). Corpus callosum thickness was normal. Kayser-Fleischer ring was absent and funduscopic exam was normal. A focused dystonia gene panel was negative. Neurodegeneration with brain iron accumulation disorders (PANK2 and PLA2G6) and Niemann-Pick disease were also ruled out. Informed consent was obtained before genetic analysis. Three years later, examination revealed mild abnormal extraocular movements with saccadic pursuit, hypometric saccades and horizontal gaze nystagmus. Speech was dysarthric with a mixed spastic/dystonic and cerebellar quality. Finger-nose and knee-toe maneuvers showed mild dysmetria. Generalized hyperreflexia and ankle clonus were easily elicited. Right cutaneous-plantar response was flexor and left was equivocal (Video 1 and Video 2). As pyramidal and cerebellar signs became evident, we decided to perform further genetic testing. We followed a stepwise approach and initially dynamic repeat expansion mutations (SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12, SCA17, DRPLA, FXN) were excluded. Subsequently HSP and hereditary cerebellar ataxia genes were analyzed using a custom gene panel.6 Two previously reported4 SPG7 pathogenic variants were found: c.1529C > T(p.Ala510Val) and c.1715C > T(p.Ala572Val). Segregation analysis demonstrated that variants affected both alleles (trans configuration). Herein we describe a genetically confirmed SPG7 case presenting with multifocal dystonia with prominent bulbar and cervical involvement. Emergence of cerebellar and pyramidal signs helped us to reach diagnosis. Patient's follow up was 8 years later. At present he is 36, and ambulatory gait is still preserved. Speech and chewing impairment are the most important symptoms. Dystonia in SPG7 is uncommon. Solely cases of focal dystonia have been reported. Cervical dystonia was present in two patients from the Dutch cohort.7 Spasmodic dysphonia was described in a patient of Pakistani origin8 and recently focal limb dystonia was added to SPG7 phenotypes.9 Cerebellar atrophy is the most frequent radiological abnormality in all hereditary ataxias. It was present at initial evaluation in our patient, reflecting that clinical or radiological signs of cerebellum involvement should guide genetic testing approach in dystonia-ataxia syndromes. The finding of bilateral cerebral peduncle T2 hyperintensities should also be observed as it has never been described before. Different studies have demonstrated that dystonia is a network disorder. Lesions not only in the basal ganglia but also in the cerebellum or in sensorimotor cortex may lead to the development of dystonia. Additionally, dystonia can be the presenting symptom in inherited cerebellar diseases and cerebellar atrophy can be found both in patients with idiopathic or familial dystonia.10 Recognition of new disease phenotypes will contribute to delineate the shared genetic background of dystonia-ataxia syndromes and also improve the yield of genetic testing. This case widens SPG7 phenotype with multifocal dystonia and shows that SPG7 should be included in the differential diagnosis of combined dystonia, especially when clinical and/or radiological pyramidal and cerebellar signs are present. 1. Research Project: A Conception, B. Organization, C. Execution; 2 Statistical Analysis A. Design, B. Execution, C Review and Critique; 3. Manuscript Preparation: A. Writing the first draft, B: Review and Critique. MCR: 1A, 1B, 1C, 2A, 2B, 3A RBM: 1A, 1B, 1C, 2A, 2B, 3A ISB: 2C, 3B LB: 2C, 3B TJ: 2C, 3B IMT: 2C, 3B We thank the patient and his family for their patience and cooperation. We thank Dr Carmen Espinós and her team at the Unit of Rare Neurodegenerative Disease in Centro de Investigación Príncipe Felipe (CIPF) for performing further genetic analysis in our patient and providing comprehensive assessment of the technical methods and results. The authors confirm that the approval of an institutional review board was not required for this work. Patient provided written informed consent for clinical information and video material use for academic purposes. 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. The authors report no sources of funding and no conflicts of interest. The authors report no sources of funding and no conflicts of interest.