Hereditary spastic paraplegia (HSP) is a heterogeneous group of inherited disorders characterized by lower limb predominant spasticity with or without weakness. HSP can be classified as uncomplicated or complicated based on the presence of other neurological or systemic features.
HSP7 is an autosomal recessive disorder caused by a mutation in the SPG7 (paraplegin) gene on chromosome 16q. It accounts for 4–12% of autosomal recessive HSP.1, 2 Onset is generally in adulthood; however, it can range from 11 to 72 years.2 HSP7 is usually complicated (69%), with cerebellar ataxia as the most frequent additional feature (57%).3 Other features include optic atrophy, ptosis, vertical supranuclear gaze palsy, hearing loss, bladder dysfunction, sensorimotor polyneuropathy, cognitive impairment, and dystonia.2, 3, 4 Dystonia is rarely seen in HSP7; to date only cervical dystonia has been reported.3
We describe a case of a 26‐year‐old man who presented with a progressive gait disorder and abnormal speech. At age 17, he began toe walking. Over time, his gait developed a limping, unsteady quality with leg stiffness and falls. At age 25, his voice became progressively hoarse and strangulated with dysphagia. He is of Pakistani origin and his parents are first cousins. His paternal uncle has intellectual disability; otherwise, there is no family history of neurological disorders.
Examination revealed spastic tone in the legs and normal strength throughout. He had diffuse hyperreflexia in the extremities with bilateral Hoffmann's reflexes, ankle clonus, and upgoing toes. He had pronounced foot plantar flexion when walking. His gait did not change when running or walking backwards. His voice had a strained quality with occasional breaks on voiced phonation. His voice quality normalized when laughing and the strain and breaks resolved with whispering (Video S1).
A brain MRI was normal. A cervical spine MRI revealed mild cord flattening. Nerve conduction studies and electromyography were normal. A laryngo‐videostroboscopy revealed normal laryngeal function with occasional spasm with connected speech, consistent with adductor spasmodic dysphonia.
Trio whole exome sequencing (WES) was performed after written informed consent was obtained through an institutional review and board‐approved research study. WES detected a homozygous, previously reported pathogenic nonsense variant p.L78X (c.233T>A) in the SPG7 gene.1, 5 Clinical Sanger sequencing confirmed the presence of the homozygous variant in the patient. One report suggested that the L78X mutation might have a dominant effect; however, a second pathogenic variant could not be excluded in that patient.5 Our patient's parents, both of whom were carriers of the L78X variant, had no subjective complaints, though neither was examined.
He is being treated with botulinum toxin injections to the thyroarytenoid muscles for adductor spasmodic dysphonia and to the bilateral gastrocnemius for gait dysfunction, thought to be a combination of spasticity and dystonia. The injections and voice therapy improved his voice.
We believe this is the first description of spasmodic dysphonia, a focal dystonia of the laryngeal muscles, in association with a SPG7 mutation. Since spasmodic dysphonia responds well to botulinum toxin injections, it is important to distinguish between it and other types of dysarthria (cerebellar and spastic), which combined are present in over one‐third of HSP7 cases.3
Author Roles
Research: Patient history and examination: D.H., M.J.P., S.L.P., O.A.L; Genetic analysis: N.S., N.L. Manuscript preparation; First draft: D.H; Review and critique: D.H., M.J.P., S.L.P., O.A.L., N.S., N.L.
Disclosures
Ethical Compliance Statement: The authors confirm that they have read the Journal's Ethical Publication Guidelines and that the manuscript conforms to these guidelines.
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: OAL‐NIH, Michael J. Fox Foundation, American Parkinson Disease Foundation, Parkinson Disease Foundation, Abbvie.
Supporting information
A video accompanying this article is available in the supporting information here.
Video S1. Segment 1 demonstrates adductor spasmodic dysphonia, with normalization of the voice quality when laughing and resolution of the strain and breaks with whispering. Segment 2 demonstrates the toe walking, spastic, and dystonic gait.
Relevant disclosures and conflicts of interest are listed at the end of this article.
References
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Supplementary Materials
A video accompanying this article is available in the supporting information here.
Video S1. Segment 1 demonstrates adductor spasmodic dysphonia, with normalization of the voice quality when laughing and resolution of the strain and breaks with whispering. Segment 2 demonstrates the toe walking, spastic, and dystonic gait.