ABSTRACT
OBJECTIVE: To assess the frequency of mutations in C19orf12 in the greater neurodegeneration with brain iron accumulation (NBIA) population and further characterize the associated phenotype. METHODS: Samples from 161 individuals with idiopathic NBIA were screened, and C19orf12 mutations were identified in 23 subjects. Direct examinations were completed on 8 of these individuals, and medical records were reviewed on all 23. Histochemical and immunohistochemical studies were performed on brain tissue from one deceased subject. RESULTS: A variety of mutations were detected in this cohort, in addition to the Eastern European founder mutation described previously. The characteristic clinical features of mitochondrial membrane protein-associated neurodegeneration (MPAN) across all age groups include cognitive decline progressing to dementia, prominent neuropsychiatric abnormalities, and a motor neuronopathy. A distinctive pattern of brain iron accumulation is universal. Neuropathologic studies revealed neuronal loss, widespread iron deposits, and eosinophilic spheroidal structures in the basal ganglia. Lewy neurites were present in the globus pallidus, and Lewy bodies and neurites were widespread in other areas of the corpus striatum and midbrain structures. CONCLUSIONS: MPAN is caused by mutations in C19orf12 leading to NBIA and prominent, widespread Lewy body pathology. The clinical phenotype is recognizable and distinctive, and joins pantothenate kinase-associated neurodegeneration and PLA2G6-associated neurodegeneration as one of the major forms of NBIA.
Subject(s)
Iron Overload/genetics , Neurodegenerative Diseases/genetics , Neurodegenerative Diseases/pathology , Adolescent , Adult , Brain Chemistry/genetics , Child , Child, Preschool , Cohort Studies , DNA/genetics , Dystonia/etiology , Electroencephalography , Electromyography , Fecal Incontinence/etiology , Female , Gait Disorders, Neurologic/etiology , Humans , Immunohistochemistry , Iron Overload/diagnostic imaging , Iron Overload/pathology , Lewy Body Disease/pathology , Male , Mitochondrial Proteins/genetics , Mutation , Neurodegenerative Diseases/complications , Neurodegenerative Diseases/diagnostic imaging , Neurologic Examination , Phenotype , Radiography , Urinary Incontinence/etiology , Young AdultABSTRACT
Drop attacks are sudden spontaneous falls that are not accompanied by alteration of consciousness and are followed by immediate recovery. Cataplexy, which is usually associated with narcolepsy, is one of the causes of drop attacks. We report a patient with the rare condition of cataplexy without associated narcolepsy (isolated cataplexy). Isolated cataplexy should be included in the differential diagnosis when a patient presents with recurrent drop attacks and normal diagnostic test results.
ABSTRACT
A number of medications have been used with varying success to treat the symptoms of generalized, focal, and paroxysmal dyskinesias; these agents include anticonvulsant, benzodiazepine, neuroleptic, dopaminergic, dopamine antagonist, and carbonic anhydrase inhibitor types. The carbonic anhydrase inhibitor drug group is best represented by acetazolamide, which has been widely applied in the treatment of paroxysmal dyskinesias. Zonisamide, which has several putative pharmacologic mechanisms of action, is a member of the carbonic anhydrase inhibitor drug group. Zonisamide was chosen for treatment of secondary paroxysmal dystonia in a patient with pyruvate dehydrogenase deficiency (case 1) and in two patients with neonatal hemochromatosis and family history of neonatal hemochromatosis (cases 2 and 3). Although zonisamide ameliorated the symptoms of secondary paroxysmal dystonia in these three patients, the precise biochemical mechanism remains unclear, and further studies are needed to substantiate and explain this finding.
Subject(s)
Antioxidants/therapeutic use , Dystonic Disorders/drug therapy , Isoxazoles/therapeutic use , Adolescent , Child , Female , Hemochromatosis/complications , Hemochromatosis/drug therapy , Humans , Male , Pyruvate Dehydrogenase Complex Deficiency Disease/complications , Pyruvate Dehydrogenase Complex Deficiency Disease/drug therapy , ZonisamideABSTRACT
BACKGROUND: Gillespie syndrome is a rare variant form of aniridia, characterized by mental retardation, nonprogressive cerebellar ataxia, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there have been no associated PAX6 mutations or Wilms' tumor reported in Gillespie syndrome patients. Ocular findings in 21 cases published since Gillespie's initial description in 1965 include iris and foveal hypoplasia, nystagmus, and small optic discs with pigmentary retinopathy. CASE REPORT: We herein report a case of atypical Gillespie syndrome associated with bilateral ptosis, exotropia, corectopia, iris hypoplasia, anterior capsular lens opacities, foveal hypoplasia, retinal vascular tortuosity, and retinal hypopigmentation. Neurologic evaluation revealed a mild hand tremor and learning disability, but no ataxia or cerebellar abnormalities on neuroimaging. Sequencing studies revealed a substitution in intron 2 of the PAX6 gene (IVS2 + 2T > A). To our knowledge, this is the first mutation of PAX6 gene reported in association with a Gillespie-like syndrome.
