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.

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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.

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QSART (quantitative sudomotor axon reflex testing) was performed in a patient with idiopathic pure sudomotor failure. Generalized reduction in thermoregulatory sweating and complete absence of axon reflex sweating were observed, suggesting a deficit of sweat gland cholinergic synaptic transmission or receptors. QSART responded promptly to treatment. Putative pathophysiological mechanisms are discussed.

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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 proband's younger brother exhibited myopathy and dementia. To our knowledge, this is the first report of genetically confirmed heterozygote OPMD associated with dementia.

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