We report genetically confirmed heterozygote oculopharyngeal muscular dystrophy (OPMD) accompanied by dementia, suggesting a possible causal association between OPMD and dementia. The proband first noticed bilateral ptosis, dysphagia, and proximal dominant muscle weakness in the lower extremities at age 53. Ten years later, she was found to have dementia with a score of 10/30 on the mini-mental state examination (MMSE). On PABPN1 gene analysis, the GCN repeat was expanded 17 times in one allele. In addition, the probands younger brother exhibited myopathy and dementia. To our knowledge, this is the first report of genetically confirmed heterozygote OPMD associated with dementia.
A 78-year-old man was admitted to our hospital with repeated attacks of headache and visual hallucinations, which had begun 10 days before. He also displayed left hemispatial neglect and left homonymous hemianopsia during attacks. Brain magnetic resonance imaging (MRI) showed an abnormal high-intense area in the right occipital lobe on diffusion weighted imaging (DWI) and fluid attenuated inversion recovery (FLAIR) weighted imaging; this lesion was demonstrated as an area of hyperperfusion on ECD-single photon emission computed tomography (SPECT) and hypoperfusion on 123I-BZ-SPECT. Electroencephalography during an attack demonstrated epileptogenic discharges in the right occipital region. Acute urinary retention due to meningoencephalitis appeared 2 weeks after onset of the first attack. Autoantibodies against glutamate receptor epsilon2 were detected in cerebrospinal fluid. We diagnosed the patient with occipital epilepsy due to anti-NMDA receptor antibody encephalitis. Epileptic attacks diminished and MRI and SPECT findings improved following two administrations of intravenous bolus steroid therapy.
Congenital muscular dystrophy is a heterogeneous group of inherited muscle diseases characterized clinically by muscle weakness and hypotonia in early infancy. A number of genes harboring causative mutations have been identified, but several cases of congenital muscular dystrophy remain molecularly unresolved. We examined 15 individuals with a congenital muscular dystrophy characterized by early-onset muscle wasting, mental retardation, and peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center on muscle biopsy, and we have identified homozygous or compound heterozygous mutations in the gene encoding choline kinase beta (CHKB). This is the first enzymatic step in a biosynthetic pathway for phosphatidylcholine, the most abundant phospholipid in eukaryotes. In muscle of three affected individuals with nonsense mutations, choline kinase activities were undetectable, and phosphatidylcholine levels were decreased. We identified the human disease caused by disruption of a phospholipid de novo biosynthetic pathway, demonstrating the pivotal role of phosphatidylcholine in muscle and brain.
We report an adolescent case of late-onset riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency (MADD) characterized by intermittent nausea and depressive state as early symptoms. At the age of 12 years and 11 months, the patient experienced intermittent nausea and vomiting, and depressive state. She was on medication for depression for 5 months but it was ineffective. Brain magnetic resonance imaging showed disseminated high-intensity areas in the periventricular white matter and in the splenium of the corpus callosum on T2-weighted images and fluid-attenuated inversion-recovery images. Progressive muscle weakness occurred and blood creatine kinase level was found to be elevated. The muscle biopsy revealed lipid storage myopathy. Urine organic acid analysis and mutation analysis of the ETFDH gene confirmed the diagnosis of MADD. With oral supplements of riboflavin and l-carnitine, in addition to a high-calorie and reduced-fat diet, her clinical symptoms improved dramatically. Early diagnosis is important because riboflavin treatment has been effective in a significant number of patients with MADD.
A 75-year-old woman was admitted with a history of acute muscle weakness of her legs for two weeks. Physical examination showed no abnormal findings. Neurological examination revealed symmetrical proximal muscle weakness of legs with muscle pain on grasping. Laboratory data showed normal serum creatine kinase level and marked increases in the levels of serum ACE and soluble interleukin 2. Electromyography showed no myopathic changes. MRI T2 weighted imaging (T2WI) imaging for femoral skeletal muscle demonstrated scattered high and low intensity signals. Muscle biopsy from the right rectus femoris muscle showed granuloma with giant cells of Langhans. She was given a diagnosis of sarcoid myopathy, and motor weakness and abnormal intensity signals on T2WI in this patient were dramatically improved with oral administration of prednisolone (40 mg/day).
Causative genes have been identified only in four types of lipid storage myopathies (LSMs): SLC22A5 for primary carnitine deficiency (PCD); ETFA, ETFB, and ETFDH for multiple acyl-coenzyme A dehydrogenation deficiency (MADD); PNPLA2 for neutral lipid storage disease with myopathy (NLSDM); and ABHD5 for neutral lipid storage disease with ichthyosis. However, the frequency of these LSMs has not been determined. We found mutations in only 9 of 37 LSM patients (24%): 3 in SLC22A5; 4 in MADD-associated genes; and 2 in PNPLA2. This low frequency suggests the existence of other causative genes. Muscle coenzyme Q(10) levels were normal or only mildly reduced in two MADD patients, indicating that ETFDH mutations may not always be associated with CoQ(10) deficiency. The 2 patients with PNPLA2 mutations had progressive, non-episodic muscle disease with rimmed vacuoles. This suggests there is a different pathomechanism from other LSMs.
Multiple acyl-CoA dehydrogenase deficiency (MADD) is a metabolic disorder due to dysfunction of electron transfer flavoprotein (ETF) or ETF-ubiquinone oxidoreductase (ETF-QO). Mutations in ETFDH, encoding ETF-QO have been associated with both riboflavin-responsive and non-responsive MADD as well as a myopathic form of CoQ(10) deficiency, although pathomechanisms responsible for these different phenotypes are not well-defined. We performed mutation analysis in four Taiwanese MADD patients. Three novel ETFDH mutations were identified in four patients and all harbored the p.A84T mutation. Muscle CoQ(10) levels and respiratory chain activities measured in two patients were normal. Three patients improved on riboflavin together with carnitine. Our results show that not all MADD patients have CoQ(10) deficiency. Based upon our data, riboflavin and carnitine may be the first-line treatment for MADD.
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