Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.

BACKGROUND: The genetic cause of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which is characterized by ischemic, nonhypertensive, cerebral small-vessel disease with associated alopecia and spondylosis, is unclear. METHODS: In five families with CARASIL, we carried out linkage analysis, fine mapping of the region implicated in the disease, and sequence analysis of a candidate gene. We also conducted functional analysis of wild-type and mutant gene products and measured the signaling by members of the transforming growth factor beta (TGF-beta) family and gene and protein expression in the small arteries in the cerebrum of two patients with CARASIL. RESULTS: We found linkage of the disease to the 2.4-Mb region on chromosome 10q, which contains the HtrA serine protease 1 (HTRA1) gene. HTRA1 is a serine protease that represses signaling by TGF-beta family members. Sequence analysis revealed two nonsense mutations and two missense mutations in HTRA1. The missense mutations and one of the nonsense mutations resulted in protein products that had comparatively low levels of protease activity and did not repress signaling by the TGF-beta family. The other nonsense mutation resulted in the loss of HTRA1 protein by nonsense-mediated decay of messenger RNA. Immunohistochemical analysis of the cerebral small arteries in affected persons showed increased expression of the extra domain-A region of fibronectin and versican in the thickened tunica intima and of TGF-beta1 in the tunica media. CONCLUSIONS: CARASIL is associated with mutations in the HTRA1 gene. Our findings indicate a link between repressed inhibition of signaling by the TGF-beta family and ischemic cerebral small-vessel disease, alopecia, and spondylosis.

Muscle MRI in myotonic dystrophy type 1 with foot drop.

The purpose of this study was to investigate the relationship of muscle MRI findings and gait disturbance in myotonic dystrophy type 1 (DM1) patients. Thirteen patients with DM1 were evaluated by manual muscle strength test and muscle MRI of the lower limb. All DM1 patients presenting with foot drop showed high intensity signals in the tibialis anterior muscles on T1-weighted imaging (p < 0.001). The patients presenting with gait disturbance showed high intensity signals in the semimembranosus, vastus intermedius and gastrocnemius medialis muscles, too. Disturbance of the gastrocnemius lateralis muscles was mild in all DM1 patients. The patients without gait disturbance showed no abnormalities, especially in tibialis anterior muscles on muscle MRI. Muscle MRI is useful for the detection of pathological muscles in DM1 patients with gait disturbance.

MM2-cortical-type sporadic Creutzfeldt-Jakob disease with early stage cerebral cortical pathology presenting with a rapidly progressive clinical course.

We report the case of a 67-year-old man with MM2-cortical-type sporadic Creutzfeldt-Jakob disease (sCJD) with a rapidly progressive clinical course of 5 months. Initial symptoms were progressive memory disturbance and dementia. MRI revealed high signal-intensity lesions on diffusion-weighted images in the bilateral frontal and occipital cortices. Myoclonus and periodic sharp-wave complexes on the electroencephalogram were observed in the early disease stage. The clinical diagnosis was typical sCJD. Neuropathologic examination at autopsy showed widespread, characteristic cerebral neocortical involvement with large confluent vacuole-type spongiform change. Spongiform degeneration was also evident in the striatum and medial thalamus. In the cerebellar cortex, slight depletion of Purkinje neurons was evident without spongiform change in the molecular layer or apparent neuron loss in the granule cell layer. The inferior olivary nucleus showed slight hypertrophic astrocytosis without neuron loss. Prion protein (PrP) immunostaining showed widespread, characteristic perivacuolar-type PrP deposits with irregular plaque-like PrP deposits in the cerebral neocortex, striatum and medial thalamus. We believe this patient showed early-stage cerebral cortical pathology of MM2-cortical-type sCJD, which may provide clues regarding the pathologic progression of this rare sCJD subtype. Although MM2-cortical-type sCJD generally shows slow progression without myoclonus or periodic sharp-wave complexes, the present patient showed a rapidly progressive clinical course similar to that of MM1-type sCJD.

Characteristic features and progression of abnormalities on MRI for CARASIL.

OBJECTIVES: The objective of this study was to clarify the characteristic brain MRI findings for genetically diagnosed CARASIL (cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy). METHODS: Seven patients with CARASIL carrying HTRA1 mutations (representing 6 Japanese families) were included in this study. Eighteen brain MRIs were reviewed and evaluated with a new rating scale based on scoring for abnormal hyperintense lesions and atrophy. RESULTS: At the last follow-up MRI, all patients had hyperintense lesions on T2-weighted images of the frontal white matter, anterior temporal lobe, external capsules, and thalami. Patients with longer time from the onset of cognitive impairment had higher MRI severity score. The atrophy advanced, followed by white matter lesion progression. During the early stage, hyperintense lesions were observed in the frontal white matter, external capsule, and pons. During the late stage, the arc-shaped hyperintense lesion from the pons to the middle cerebellar peduncles, which we designated the "arc sign," became evident. The arc sign was a characteristic finding for CARASIL in the advanced stage. CONCLUSIONS: These characteristic MRI findings for CARASIL are useful for selecting patients for genetic testing. The rating scale correlates well with disease duration and might be useful for assessing disease progression.

Muscle MRI findings of X-linked spinal and bulbar muscular atrophy.

We report here muscle MRI findings of the lower limb in X-linked spinal and bulbar muscular atrophy (SBMA). T1-weighted imaging of muscle MRI disclosed that the thigh muscles, including the semimembranosus, biceps femoris longus and the vastus lateralis muscles, showed high intensity signals with atrophy. Contrarily, the sartorius, gracilis and rectus femoris muscles were comparably preserved. Not only the thigh muscles, but also the calf muscles including the gastrocnemius medialis and lateralis, and soleus muscles showed high intensity signals. In amyotrophic lateral sclerosis (ALS), the leg muscles are generally atrophic, but the selective pattern of fatty degeneration, seen in SBMA was not observed. Muscle MRI is a useful method of estimating the distribution and severity of SBMA in affected muscles.

Muscle MRI findings of HTLV-1-associated myelopathy.

We report here the muscle MRI findings in two patients with human T-cell lymphotropic virus type I-associated myelopathy (HAM). It is known that thigh muscles are vulnerable in HAM patients, but detailed information about the affected muscles has not been available. Muscle MRI findings of these patients showed that thigh muscles, especially adductor magnus, and semimembranosus muscles were severely affected, but lower leg muscles were comparatively preserved. In these affected muscles, neurogenic changes were observed by EMG. We concluded that muscle MRI is very useful to estimate the affected muscles in HAM patients.

Winged scapula in patients with myotonic dystrophy type 1.

We report two patients with myotonic dystrophy type 1 (DM1) showing winged scapula in a single family. Genomic analysis revealed a marked expansion of CTG repeats in the 3' untranslated region; 1100 in patient 1 and 667 in patient 2. Muscle MRI revealed marked atrophy in the serratus anterior muscle in both patients. Muscle biopsy findings showed central nuclei and variations in fiber size. One of the patients showed ragged red fibers in muscles of the biceps brachii. To our knowledge, this is the first report of typical winged scapula in DM1.

[An autopsy case of cryptococcal meningoencephalitis with AIDS: correspondence between MRI and pathological findings of basal ganglia and cerebellum].

We reported a 71-year-old male who showed subacute progression in cognitive decline and gait disturbance. Cystic lesions in the basal ganglia and a high signal in the right cerebellar hemisphere were detected respectively on MRI fluid-attenuated inversion recovery (FLAIR) image and diffusion weighted image (DWI) taken at 7 days after admission to our hospital. Dilatation of the Virchow-Robin space and fresh cerebellar infarction were suspected. Since an examination of cerebrospinal fluid (CSF) did not reveal any significant features, diagnosis of this patient proved very difficult. His cellular immunodeficiency was detected by bone marrow aspiration, so he was diagnosed as suffering from acquired immunodeficiency syndrome (AIDS). Six months after onset, the patient died from sepsis and respiratory failure. Pathological findings revealed multiple cryptococcus in the cystic lesions of the basal ganglia and cerebellum. There was little infiltration of inflammatory cells while pathological findings did not demonstrate any AIDS encephalopathy or vascular disorders. We speculated that subacute progression in cognitive decline and gait disturbance had been caused by cryptococcal meningoencephalitis and secondary normal pressure hydrocephalus (NPH). Cryptococcal meningoencephalitis in patients with AIDS is often accompanied by normal CSF as a result of cellular immunodeficiency, therefore diagnosis needs to be very careful. Particular attention needs to be paid to the existence of cryptococcal meningoencephalitis when patients show subacute progression in cognitive decline and cystic lesions in the basal ganglia present themselves on MRI.