Novel Homozygous Variant in COQ7 in Siblings With Hereditary Motor Neuropathy.

Background and Objectives: Coenzyme Q10 (CoQ10) is an important electron carrier and antioxidant. The COQ7 enzyme catalyzes the hydroxylation of 5-demethoxyubiquinone-10 (DMQ10), the second-to-last step in the CoQ10 biosynthesis pathway. We report a consanguineous family presenting with a hereditary motor neuropathy associated with a homozygous c.1A > G p.? variant of COQ7 with abnormal CoQ10 biosynthesis. Methods: Affected family members underwent clinical assessments that included nerve conduction testing, histologic analysis, and MRI. Pathogenicity of the COQ7 variant was assessed in cultured fibroblasts and skeletal muscle using a combination of immunoblots, respirometry, and quinone analysis. Results: Three affected siblings, ranging from 12 to 24 years of age, presented with a severe length-dependent motor neuropathy with marked symmetric distal weakness and atrophy with normal sensation. Muscle biopsy of the quadriceps revealed chronic denervation pattern. An MRI examination identified moderate to severe fat infiltration in distal muscles. Exome sequencing demonstrated the homozygous COQ7 c.1A > G p.? variant that is expected to bypass the first 38 amino acid residues at the n-terminus, initiating instead with methionine at position 39. This is predicted to cause the loss of the cleavable mitochondrial targeting sequence and 2 additional amino acids, thereby preventing the incorporation and subsequent folding of COQ7 into the inner mitochondrial membrane. Pathogenicity of the COQ7 variant was demonstrated by diminished COQ7 and CoQ10 levels in muscle and fibroblast samples of affected siblings but not in the father, unaffected sibling, or unrelated controls. In addition, fibroblasts from affected siblings had substantial accumulation of DMQ10, and maximal mitochondrial respiration was impaired in both fibroblasts and muscle. Discussion: This report describes a new neurologic phenotype of COQ7-related primary CoQ10 deficiency. Novel aspects of the phenotype presented by this family include pure distal motor neuropathy involvement, as well as the lack of upper motor neuron features, cognitive delay, or sensory involvement in comparison with cases of COQ7-related CoQ10 deficiency previously reported in the literature.

Bilateral Vocal Cord Paralysis and Cervicolumbar Radiculopathy as the Presenting Paraneoplastic Manifestations of Small Cell Lung Cancer: A Case Report and Literature Review.

Introduction. Bilateral vocal cord paralysis (BVCP) is a potential medical emergency. The Otolaryngologist plays a crucial role in the diagnosis and management of BVCP and must consider a broad differential diagnosis. We present a rare case of BVCP secondary to anti-Hu paraneoplastic syndrome. Case Presentation. A 58-year-old female presented to an Otolaryngology clinic with a history of progressive hoarseness and dysphagia. Flexible nasolaryngoscopy demonstrated BVCP. Cross-sectional imaging of the brain and vagus nerves was negative. An antiparaneoplastic antibody panel was positive for anti-Hu antibodies. This led to an endobronchial biopsy of a paratracheal lymph node, which confirmed the diagnosis of small cell lung cancer. Conclusion. Paraneoplastic neuropathy is a rare cause of BVCP and should be considered when more common pathologies are ruled out. This is the second reported case of BVCP as a presenting symptom of paraneoplastic syndrome secondary to small cell lung cancer.

Myasthenia Gravis Treated With Autologous Hematopoietic Stem Cell Transplantation.

IMPORTANCE: Some patients with myasthenia gravis (MG) do not respond to conventional treatment and have severe or life-threatening symptoms. Alternate and emerging therapies have not yet proved consistently or durably effective. Autologous hematopoietic stem cell transplant (HSCT) has been effective in treating other severe autoimmune neurologic conditions and may have similar application in MG. OBJECTIVE: To report 7 cases of severe MG treated with autologous HSCT in which consistent, durable, symptom-free, and treatment-free remission was achieved. DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study reports outcomes at The Ottawa Hospital, a large, Canadian, tertiary care referral center with expertise in neurology and HSCT, from January 1, 2001, through December 31, 2014, with a median follow-up of 40 months (range, 29-149 months). Data collection and analysis were performed from February 1 through August 31, 2015. All patients with MG treated with autologous HSCT at The Ottawa Hospital were included. All had persistent severe or life-threatening MG-related symptoms despite continued use of intensive immunosuppressive therapies. INTERVENTIONS: Autologous hematopoietic stem cell grafts were mobilized with cyclophosphamide and granulocyte colony-stimulating factor, collected by peripheral blood leukapheresis, and purified away from contaminating lymphocytes using CD34 immunomagnetic selection. Patients were treated with intensive conditioning chemotherapy regimens to destroy the autoreactive immune system followed by graft reinfusion for blood and immune reconstitution. MAIN OUTCOMES AND MEASURES: The primary outcome was MG disease activity after autologous HSCT measured by frequency of emergency department visits and hospitalizations and Myasthenia Gravis Foundation of America (MGFA) clinical classification, MGFA therapy status, and MGFA postintervention status. Safety outcomes included all severe autologous HSCT-related complications. RESULTS: Seven patients underwent autologous HSCT, 6 for MG and 1 for follicular lymphoma with coincident active MG. Mean (SD) ages at MG diagnosis and at autologous HSCT were 37 (11) and 44 (10) years, respectively. Five patients (71%) had concurrent autoimmune or lymphoproliferative illnesses related to immune dysregulation. All patients had distinct clinical and electromyographic evidence of MG (MGFA clinical classification IIIb-V). All patients achieved durable MGFA complete stable remission with no residual MG symptoms and freedom from any ongoing MG therapy (MGFA postintervention status of complete stable remission). Three patients (43%) experienced transient viral reactivations, and 1 (14%) developed a secondary autoimmune disease after autologous HSCT, all of which resolved or stabilized with treatment. There were no treatment- or MG-related deaths. CONCLUSIONS AND RELEVANCE: Autologous HSCT results in long-term symptom- and treatment-free remission in patients with severe MG. The application of autologous HSCT for this and other autoimmune neurologic conditions warrants prospective study.

Autologous stem cell transplantation for stiff person syndrome: two cases from the Ottawa blood and marrow transplant program.

IMPORTANCE: Stiff person syndrome (SPS) is a rare neurological disease causing significant functional disability for patients and presenting a therapeutic challenge for clinicians. Autologous hematopoietic stem cell transplantation (auto-HSCT) has been used successfully to remit autoimmune-mediated neurological diseases. We report 2 cases of severe SPS treated with auto-HSCT, a novel therapy for this disease. OBSERVATIONS: Two anti-glutamic acid decarboxylase antibody-positive patients with SPS had an autologous hematopoietic stem cell graft collected and stored. Subsequently, the patients underwent auto-HSCT. Both patients achieved clinical remission with sustained, marked improvement in symptoms and a return to premorbid functioning, now more than 2.5 and 4.5 years after the procedure. CONCLUSIONS AND RELEVANCE: Stiff person syndrome represents a novel indication for auto-HSCT. The resolution of clinical manifestations of SPS despite the persistence of anti-glutamic acid decarboxylase antibodies following auto-HSCT suggests that the antibody does not play a direct role in pathogenesis of SPS.