Camptocormia and shuffling gait due to a novel MT-TV mutation: Diagnostic pitfalls
نویسندگان
چکیده
Camptocormia, the disabling flexion of the spine in upright, but not supine position, has been reported in a range of central nervous and neuromuscular conditions and is associated with aging, too. In many cases, e.g., Parkinson disease, further clinical symptoms will clarify its association, if not pathophysiology. In others, a tangle of signs and symptoms obscures the etiology. Here, we present a new solution to this challenging and complex clinical problem. A 71-year-old Caucasian woman presented with a 3-year history of unstable, short-stepping slow, shuffling gait and complained of deteriorating handwriting. Her medical history included basalioma, malignant melanoma, hypothyreosis, bilateral cataract and hypoacusis, gastroesophageal reflux, prediabetes, and thoracal and lumbal disc herniation. While her mother and a brother suffer from type II diabetes and a sister has a thyroid disorder, no other recurrent, neuromuscular, or movement disorders are known in the family. A brother died in childhood of unclear causes, a further brother in adulthood of a liver condition. Her son, daughter, and 2 grandsons are well. Clinical examination revealed slow horizontal saccades. Deep tendon reflexes were brisk, but for diminished ankle reflexes. Babinski response was equivocal on the right. Muscle tone and bulk appeared normal, but there was weakness of proximal lower limb muscles and foot extensors (MRC 4). Steps were short and their number for 180° turn increased. Positive Romberg test and inability to tandem walking suggested sensory ataxia, but sensory examination was otherwise normal. At follow-up, a slightly stooped posture progressed into camptocormia (figure, A) without signs of dystonia or muscle rigidity. Mild weakness of proximal arm muscles was found. Spinal MRI showed cervical stenosis without signs of myelopathy, but fatty replacement of paraspinal muscles. Initial neurophysiologic examinations showed prolonged cortical latency after tibial nerve stimulation, but transcranial stimulation gave normal total and central motor conduction times, and EMG of the vastus lateralis muscle was normal. Repeated neurography revealed a mild sensorimotor polyneuropathy. Levodopa treatment and CSF drainage under the suspicion of Parkinson disease or normal pressure hydrocephalus (NPH) due to enlarged lateral ventricles in an otherwise unremarkable brain MRI and urge incontinence were unsuccessful. DAT scan, EEG, Holter ECG, blood pressure monitoring, orthostatic test, and CSF analysis, including biomarkers for neurodegeneration (beta-amyloid, tau, and phospho-tau), revealed no abnormalities. Mini-Mental State examination and Montreal Cognitive Assessment indicated mild cognitive impairment. Maximum serum creatine kinase was 236 U/L (,170 U/L). Genetic and antibody analysis ruled out facioscapulohumeral muscular dystrophy types 1 and 2 as well as myasthenic syndromes, respectively. Biceps brachii muscle biopsy showed angular atrophic fibers, a few degenerating fibers and increased lipofuscin deposition. Modified Gomori trichrome staining and oxidative enzyme reactions revealed ragged red fibers and ;6% cytochrome c oxidase (COX)-deficient fibers (figure, B). Occasional ragged red fibers appeared COX positive. In skeletal muscle tissue homogenate, activities of mitochondrial respiratory chain complexes I and IV normalized against citrate synthase activity were mildly decreased to 0.07 (controls: 0.11 6 0.03 [n5 11]) and 1.38 (2.76 0.5 [n5 11]) U/g, respectively, while quadruple OXPHOS immunofluorescence confirmed the presence of fibers lacking both complex I (NDUFB8) and complex IV (COX-1) expression, confirming a multiple respiratory chain defect (figure, C). Mitochondrial DNA (mtDNA) sequencing revealed a previously unreported heteroplasmic m.1660G.A MT-TV variant present at highest levels in the muscle (35% mutation load), with lower levels in urinary epithelial sediments (13%) and blood (9%), consistent with the segregation pattern of a pathogenic mtDNA mutation. Single-fiber segregation studies clearly confirmed pathogenicity, showing a statistically significant higher m.1660G.A mutation load in COX-deficient fibers (94.306 0.76 [n5 20]) than in COX-positive fibers (22.176 6.49 [n 5 18], p , 0.0001, unpaired t test) (figure, D).
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