Extramuscular manifestations in children with severe congenital myopathy due to ACTA1 gene mutations.

We examined three patients with a severe infantile type of congenital myopathy due to dominant, missense ACTA1 mutations. In addition to muscle weakness, all three patients showed developmental delay in word comprehension during early childhood. All also showed frontal lobe hypoplasia and lateral ventricular dilatation. One patient in addition exhibited features of multiple congenital malformations including skeletal dysplasia, hepatomegaly and urinary tract stenosis. These findings may suggest a link between extramuscular expression of α-skeletal muscle actin and clinical symptoms in non-skeletal muscle tissues of patients with ACTA1 mutations, and probably a functional role of α-skeletal muscle actin during fetal development.

Post-streptococcal chorea in an adult with bilateral striatal encephalitis.

We present distinctive MRI findings in an adult female patient with possible Sydenham's chorea. T2-weighted MRI showed bilaterally symmetric, diffusely homogenous, and clearly demarcated hyperintensities selectively involving the entire striatum with swelling of the bilateral caudate heads. The MRI features may reflect the pathogenetic mechanisms of Sydenham's chorea associated with a specific autoimmune response to the basal ganglia.

Congenital myotonic dystrophy can show congenital fiber type disproportion pathology.

Congenital myotonic dystrophy (CDM) is associated with markedly expanded CTG repeats in DMPK. The presence of numerous immature fibers with peripheral halo is a characteristic feature of CDM muscles together with hypotrophy of type 1 fibers. Smaller type 1 fibers with no structural abnormality are a definitive criterion of congenital fiber type disproportion (CFTD). Nonetheless, we recently came across a patient who was genetically confirmed as CDM, but had been earlier diagnosed as CFTD when he was an infant. In this study, we performed clinical, pathological, and genetic analyses in infantile patients pathologically diagnosed as CFTD to evaluate CDM patients indistinguishable from CFTD. We examined CTG repeat expansion in DMPK in 28 infantile patients pathologically diagnosed as CFTD. Mutation screening of ACTA1 and TPM3 was performed, and we compared clinical and pathological findings of 20 CDM patients with those of the other cohorts. We identified four (14%) patients with CTG expansion in DMPK. ACTA1 mutation was identified in four (14%), and TPM3 mutation was found in two (7%) patients. Fiber size disproportion was more prominent in patients with ACTA1 or TPM3 mutations as compared to CFTD patients with CTG expansion. A further three patients among 20 CDM patients showed pathological findings similar to CFTD. From our results, CDM should be excluded in CFTD patients.

Human PTRF mutations cause secondary deficiency of caveolins resulting in muscular dystrophy with generalized lipodystrophy.

Caveolae are invaginations of the plasma membrane involved in many cellular processes, including clathrin-independent endocytosis, cholesterol transport, and signal transduction. They are characterized by the presence of caveolin proteins. Mutations that cause deficiency in caveolin-3, which is expressed exclusively in skeletal and cardiac muscle, have been linked to muscular dystrophy. Polymerase I and transcript release factor (PTRF; also known as cavin) is a caveolar-associated protein suggested to play an essential role in the formation of caveolae and the stabilization of caveolins. Here, we identified PTRF mutations in 5 nonconsanguineous patients who presented with both generalized lipodystrophy and muscular dystrophy. Muscle hypertrophy, muscle mounding, mild metabolic complications, and elevated serum creatine kinase levels were observed in these patients. Skeletal muscle biopsies revealed chronic dystrophic changes, deficiency and mislocalization of all 3 caveolin family members, and reduction of caveolae structure. We generated expression constructs recapitulating the human mutations; upon overexpression in myoblasts, these mutations resulted in PTRF mislocalization and disrupted physical interaction with caveolins. Our data confirm that PTRF is essential for formation of caveolae and proper localization of caveolins in human cells and suggest that clinical features observed in the patients with PTRF mutations are associated with a secondary deficiency of caveolins.

[Case of Hashimoto's encephalopathy with diffuse white matter lesions on diffusion-weighted MRI].

A 65-year-old woman was admitted to our hospital because of subacute deterioration of cognitive function. On admission, she presented with marked disorientation of time and place and inability to carry out commands. Mini-Mental State Examination score was 5/30. Although routine laboratory examinations including thyroid function, vitamin B1 and B12, serum syphilitic reaction, sIL-2 receptor level, titers of herpes simplex and zoster viruses, and HIV antibody were normal, titers of anti-thyroglobulin (TG) antibodies and thyroid peroxidase (TPO) antibodies were elevated. Cerebrospinal fluid showed normal findings. Brain MRI revealed diffuse high intensity in the white matter on diffusion- and T2-weighted images, mimicking leukoencephalopathy. We made a diagnosis of Hashimoto's encephalopathy, based on clinical features and high titers of anti-thyroid antibodies. Following administration of steroid hormone, her cognitive impairment gradually improved, associated with decrease of the white matter abnormality on MRI. Hashimoto's encephalopathy should be kept in mind in the differential diagnosis of subacute leukoencephalopathy with cognitive decline.

[A clinicoanatomical study of thalamic cheiro-oral syndrome].

We report 6 patients with Cheiro-oral syndrome (COS), with special reference to clinical features and responsible lesions. The time intervals from the onset of symptoms to arrival in our department were less than 24 hours in 3 patients, 2 days in 2, and 5 days in 1. All patients had subjective sensory disturbance involving the unilateral hand and ipsilateral perioral regions, and 4 patients presented with objective sensory disturbance. The body parts of tingling sensation tended to be larger than those of superficial sensory disturbance. Three patients developed motor disturbance including hemiparesis with or without ataxia, clumsiness of fine finger movements, and dysarthria. Magnetic resonance imaging revealed fresh infarctions around the thalamus, including lacunar infarctions in 5 patients and branch atheromatous disease in 1 patient. The lesion sites responsible for COS were ventral posterolateral (VPL) and ventral posteromedial (VPM) nuclei in the thalamus in 4 patients, thalamic pulvinar nucleus and medial geniculate body in 1, thalamic ventroposterior region-internal capsule-corona radiata in 1. Three patients had asymptomatic brain infarctions. Risk factors were hyperlipidemia, hypertension, diabetes mellitus, smoking, arteriosclerosis of the carotid artery, and polycythemia. In the convalescent stage, 5 patients suffered from residual sensory-motor disturbance, whereas 1 patient recovered from COS. COS has been attributed mainly to small infarctions in the thalamic ventroposterior nuclei. However, it is suggested that damage to ascending sensory fibers projecting to the thalamic VPL and VPM nuclei can cause COS. Because initial symptoms of COS are apt to be overlooked, early diagnosis and treatment are necessary to avoid residual sensory-motor disturbance.