Phenotype–genotype correlations of PIGO deficiency with variable phenotypes from infantile lethality to mild learning difficulties

Inherited GPI (glycosylphosphatidylinositol) deficiencies (IGDs), a recently defined group of diseases, show a broad spectrum of symptoms. Hyperphosphatasia mental retardation syndrome, also known as Mabry syndrome, is a type of IGDs. There are at least 26 genes involved in the biosynthesis and transport of GPI‐anchored proteins; however, IGDs constitute a rare group of diseases, and correlations between the spectrum of symptoms and affected genes or the type of mutations have not been shown. Here, we report four newly identified and five previously described Japanese families with PIGO (phosphatidylinositol glycan anchor biosynthesis class O) deficiency. We show how the clinical severity of IGDs correlates with flow cytometric analysis of blood, functional analysis using a PIGO‐deficient cell line, and the degree of hyperphosphatasia. The flow cytometric analysis and hyperphosphatasia are useful for IGD diagnosis, but the expression level of GPI‐anchored proteins and the degree of hyperphosphatasia do not correlate, although functional studies do, with clinical severity. Compared with PIGA (phosphatidylinositol glycan anchor biosynthesis class A) deficiency, PIGO deficiency shows characteristic features, such as Hirschsprung disease, brachytelephalangy, and hyperphosphatasia. This report shows the precise spectrum of symptoms according to the severity of mutations and compares symptoms between different types of IGD.     

Melanocytoma of the left optic nerve head and right retrobulbar optic neuropathy compressed by a tuberculum sellae meningioma

A 40-year-old woman had a highly pigmented, slightly elevated tumor on the left optic disc. She had no visual disturbance in the left eye. The tumor was stationary for 5 years. At age 45 years, she complained of decreased visual acuity in the right eye. Magnetic resonance imaging showed a right-shifted homogeneous lesion at the tuberculum sellae. Histopathologic study of the excised lesion revealed interlacing bundles of spindle-shaped fibroblast-like cells with whorl formation. We believe that a relationship between melanocytoma of the optic nerve head and a tuberculum sellae meningioma may exist rather than a chance occurrence, as previously suggested by others.     

Rhodopsin gene codon 106 mutation (Gly-to-Arg) in a Japanese family with autosomal dominant retinitis pigmentosa

PURPOSE: To examine rhodopsin gene mutations in Japanese patients with retinitis pigmentosa. METHODS: We performed a mutational analysis of the rhodopsin gene in 42 patients from 40 families with retinitis pigmentosa. Genomic DNA was amplified by polymerase chain reaction (PCR) and the PCR products were sequenced. Restriction enzyme analysis was performed in family members of 1 patient with a rhodopsin gene mutation (Gly106Arg) and in 100 normal individuals. RESULTS: Among the patients with retinitis pigmentosa, 3 patients in one family had a heterozygous Gly106Arg mutation of the rhodopsin gene. They had night blindness and sectorial retinal dystrophy (predominantly at the inferior fundus) in both eyes. None of the 100 individuals with normal fundi had the Gly106Arg mutation of the rhodopsin gene. CONCLUSION: The Gly106Arg mutation of the rhodopsin gene has been found in Japanese patients with sectorial retinitis pigmentosa.     

Hyperamino-acidaemia and hyperammonaemia in epileptic children treated with valproic acid

Serum amino acid pattern, blood ammonia, and serum valproic acid (VPA) levels were estimated in 75 epileptic children with and without VPA therapy. The incidence of patients with hyperammonaemia (>60 mol/l) in patients treated with only VPA or with a combination of VPA and other antiepileptic drugs was 19% and 20% respectively. Hyperammonaemia was not observed in patients receiving other drugs. Elevated levels of serum glycine, alanine and serine were more common in epileptic patients treated with VPA alone and with VPA in combination with other drugs than in patients receiving other drugs. A significant positive correlation was found between the serum levels of glycine and alanine, of glycine and serine, and of serine and alanine. These findings may indicate a mitochondrial dysfunction caused by VPA.Abbreviation VPA valproic acid     

Phthirus pubis infestation of the eyelashes and scalp hairs in a girl

A 4-year-old girl was seen because of foreign bodies on the eyelashes. Parasites and their nits were seen on the patient's eyelashes and scalp. Her parents denied having Phthirus pubis infection of the axillary, pubic, or body hair, despite confirmation of the infestation in their child. The parasites were removed and the lashes with nits were cut off at the base. The parasite was identified as P. pubis. The scalp was washed with phenothrin shampoo. One month later no P. pubis infestation was found. Removal of the parasites, cutting the lashes at the base, and using phenothrin shampoo on the scalp were effective in resolving phthiriasis.     

Fluctuation of computed tomographic findings in white matter in Alexander's disease

A Japanese boy developed febrile seizures and gait disturbance at 2 years of age and dysarthria a year later. He had generalized tonic-clonic seizures once or twice a year from the age of 4 years. Brain computed tomography (CT) showed symmetric low-density areas in the white matter of the frontal lobes. However, abnormal CT findings fluctuated occasionally, with no apparent change in clinical manifestations. Clinical evaluation at 9 years of age revealed hyper-reflexia, psychomotor retardation, megalencephaly, and slurred nasal speech. Magnetic resonance imaging showed white matter abnormalities, predominantly in the frontal lobes. He was a heterozygote of the Arg239Cys mutation of the glial fibrillary acidic protein gene and was diagnosed with Alexander's disease. Fluctuation of CT findings in white matter may reflect blood-brain barrier dysfunction in Alexander's disease.     

In vivo and in vitro evidence that cross-reactive antibodies to C-terminus of hypervariable region 1 do not neutralize heterologous hepatitis C virus

The hypervariable region 1 (HVR1) of hepatitis C virus (HCV) may contain neutralizing epitopes. A chimpanzee in whom cross-reactive anti-HVR1 antibodies had been induced by immunization was challenged with heterologous HCV for clarifying whether cross-reactive anti-HVR1 antibodies can neutralize heterologous HCV. Acute hepatitis C occurred in this chimpanzee after the challenge. Rechallenge with mixtures of the highest titer cross-reactive immune serum and heterologous HCV, after the chimpanzee had cleared the viremia, again resulted in HCV infection. Virus capture assay and inhibition of virus adsorption to susceptible cells, by the immune sera from the chimpanzee and highly cross-reactive monoclonal antibodies (mAbs) against the C-terminus of HVR1 of the challenge virus, showed that cross-reactive anti-HVR1 had no cross-neutralizing activity. The data imply that the HVR1 component is insufficient to develop an effective HCV vaccine.     

Mitochondrial myopathy,encephalopathy, lactic acidosis,and stroke-like episodes (MELAS) decrease in diastolic left ventricular function assessed by echocardiography

Summary Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) are known to be associated with cardiomyopathy. Systolic and diastolic left ventricular functions were assessed by M-mode and Doppler echocardiography in four patients with MELAS and in 14 normal controls. The interventricular septal thickness and left ventricular posterior wall thickness were greater (11.0±1.6 mm vs. 5.8±0.7 mm and 11.0±2.2 mm vs. 5.9±0.8 mm) in patients with MELAS than in a control group. Parameters of systolic left ventricular functions (ejection fraction, shortening fraction, systolic time intervals, and mean Vcf) and left ventricular dimensions were not significantly different between the two groups. To assess the diastolic function, blood flow velocity across the mitral valve was measured by Doppler echocardiography and various indexes were obtained. In patients with MELAS, the impairment of diastolic left ventricular filling was demonstrated by decrease in the following indexes: peak flow velocity in the early passive filling period (E) (0.76±0.10 m/s vs. 0.94±0.09 m/s), integrated velocity for total E (10.2±1.3 vs. 13.0±0.9), the ratio of E and late atrial filling integrated velocities (1.72±0.06 vs. 2.49±0.29).     

Ophthalmic complications in patients with malignant tumors of the nose and paranasal sinuses.

We examined 34 Japanese patients (16 men and 18 women) with malignant tumors of the nose and paranasal sinuses. Squamous cell carcinoma of the maxillary sinus was the most common tumor. During the patients' initial visits, several ophthalmic symptoms were noticed, including proptosis, epiphora, lid swelling, displacement of the globe, orbital mass, and sudden visual loss. In addition, several ocular and orbital symptoms and signs resulted from treatment with radiotherapy, chemotherapy, and surgery and from local recurrence of the tumor. Four patients underwent orbital exenteration, and one underwent evisceration. Five eyes had no light perception.