Two siblings of type 3 GM1 gangliosidosis with different clinical features and different ages of onset

We experienced two siblings of type 3 GM1 gangliosidosis. A 33-year-old woman developed dysarthria, dysbasia and bradykinesia at around the age of 30. Her 28-year-old brother showed locomotor retardation and skeletal deformity in infancy. He lost the ability to stand walk at childhood, and developed progressive dystonia. The major neurologic manifestations were parkinsonian symptoms in the elder sister, and progressive dystonia in her brother. Both had markedly reduced beta-galactosidase activity in peripheral blood lymphocyte and were diagnosed as having type 3 GM1 gangliosidosis. Gene analysis revealed that these patients were homozygotes of the adult type mutant gene. The two siblings are unique in that the clinical manifestations and the age of onset of symptoms differed markedly between them despite the same mutant gene in both cases.     

Porphyria cutanea tarda with constrictive pericarditis in a family

Two cases of familial porphyria cutanea tarda (PCT) with constrictive pericarditis are described. A 50-year-old woman and her 48-year-old younger brother were admitted because of right ventricular heart failure. Constrictive pericarditis was diagnosed by RV pressure waveform and echocardiogram. The patients were diagnosed as PCT based on clinical symptoms, histologic findings and elevated urinary excretion levels of uroporphyrin. Even to this day, over 40% of the etiology of constrictive pericarditis remains unknown. There is a possibility of overlooking porphyria cutanea tarda in constrictive pericarditis patients. This report describes the first documented cases of familial PCT with constrictive pericarditis.     

Familial Mondini dysplasia

OBJECTIVES/HYPOTHESIS: To determine the mode of inheritance of familial nonsyndromic Mondini dysplasia. Study Design: Correlative clinical genetic analysis of a single kindred. METHODS: Clinical history, physical examination, audiologic analysis, computed tomography of the temporal bones, and cytogenetic analysis. RESULTS: The male proband, three affected sisters, and an affected brother are offspring of unaffected parents. The mother and an unaffected brother have audiologic findings suggestive of heterozygous carrier status for a recessive hearing loss gene. CONCLUSIONS: Pedigree analysis indicates autosomal recessive inheritance in this family. The observed inheritance and clinical, audiologic, and radiologic findings are different from those previously described for another family with nonsyndromic Mondini dysplasia. The phenotype in this study family therefore represents a distinct subtype, indicating clinical and genetic heterogeneity of this disorder. This information should facilitate future molecular linkage analyses and genetic counselling of patients with inner ear malformations.     

Radiofrequency catheter ablation in familial paroxysmal supraventricular tachycardia due to accessory atrioventricular pathways

Radiofrequency catheter ablation (RF-CA) has been widely used to cure paroxysmal supraventricular tachycardia (PSVT). However, its use has never been reported in familial PSVT caused by an accessory atrioventricular pathway (AP), which is known as one of the typical familial cardiovascular diseases. Two cases of using RF-CA for familial PSVT due to APs are presented, in a brother and sister, supporting a potential genetic role in the developmental failure to lose the atrioventricular connection during fetal life. The sister, a 24-year-old woman, had intermittent episodes of palpitation accompanied by chest pain for 2 years. An electrophysiologic study (EPS) confirmed her clinical tachycardia was atrioventricular reentrant tachycardia (AVRT) due to a left lateral concealed AP, which was subsequently successfully ablated with RF-CA. The brother, a 22-year-old man, had a 5-year history of paroxysmal palpitation. A resting electrocardiogram showed a right bundle branch block and left axis deviation with a delta wave. During his EPS, AVRT was reproducibly induced and a manifest AP was localized and then ablated at the left posteroseptal site, resulting in disappearance of the delta wave. PSVT, however, recurred 1 month later and during a repeat EPS the tachycardia was proved to be AVRT due to a right anterior concealed AP. The right anterior AP was successfully ablated with RF-CA. Both patients remained asymptomatic for more than 3 years following the successful ablation procedures.     

Novel compound heterozygous mutations of growth hormone (GH) receptor gene in a patient with GH insensitivity syndrome

A girl with severe growth retardation had the clinical features of Laron syndrome. Her serum insulin-like growth factor-I level was completely unresponsive to exogenous GH administration. The serum GH-binding protein (GHBP) level was below the detectable limit in the patient, but it was normal in her parents and brother. Her parents and brother were normal in their height. Amplification with PCR and direct sequencing of her GH receptor gene revealed compound heterozygous mutations. The allele from her mother contained a transversion of G to T in exon 7 that could introduce a stop codon in place of a glutamic acid at amino acid 224. Another mutation was found in the allele in her father and also identified in her brother. It was a C deletion at position 981 in exon 10 that could introduce a frame shift, thereby causing the production of 20 novel amino acids (310-329) instead of the wild-type sequence, the premature termination at codon 330, and the subsequent deletion of the C terminal portion of the intracellular domain. RT-PCR of her father's lymphocytes and sequencing of its complementary DNA revealed that only the wild-type GH receptor messenger RNA was expressed in his lymphocytes, though the mechanism remains unclear. These results suggest that neither of the mutant alleles could generate a functional GH receptor, which would be consistent with the patient's severe growth retardation and undetectable serum GHBP.     

Congenital nephrogenic diabetes insipidus: a difficult diagnosis?

In five patients (a boy aged 10 years, a boy aged 3 months, his brother aged 1 week, the brother of the mother of the last-mentioned two boys who had died at the age of one, and a girl of kindergarten age) congenital nephrogenic diabetes insipidus was diagnosed. This rare syndrome (prevalence 1:500,000) is caused by renal insensitivity to the antidiuretic hormone arginine vasopressin. In infancy the symptoms of this disorder are aspecific, and the main symptoms of the disease, polyuria and polydipsia, often remain unnoticed at this young age. A simple anamnesis and a few laboratory tests should suggest the diagnosis. Early diagnosis and genetic counselling are possible as the molecular effects involved have been elucidated.     

Fatal familial insomnia: clinical and pathologic heterogeneity in genetic half brothers

We describe clinical and pathologic features of a patient with fatal familial insomnia (FFI) whose prion (PrP) genotype is D178N coupled with methionine at codon 129 on his mutant allele and valine at codon 129 on his normal allele. A cousin (genetic half brother) with identical PrP genotypes exhibited strikingly different clinical and pathologic changes. Comparison of these cousins shows the phenotypic heterogeneity of FFI and suggests that the phenotypic expression of D178N is influenced by multiple factors.     

Sibling relationship quality and adolescent delinquency: A latent growth curve approach.

The present study examined whether level and changes in sibling relationship quality and older sibling delinquency are related to level and changes in younger sibling delinquency, for brother, sister, older brother/younger sister and older sister/younger brother sibling pairs. Questionnaire data were collected from 249 Dutch sibling pairs (11–15 years old) over a period of three years, with annual measurements. Results showed that level and over-time changes in sibling relationship quality and older and younger sibling delinquency were significantly different for the four sibling gender combinations. Results of multivariate growth curve modeling showed that sibling relationship quality was related to delinquency of older siblings (but not younger siblings), and delinquency of older siblings was associated with younger sibling delinquency two years later. We also found differences between the four sibling gender combinations. For example, for brother and sister pairs (but not mixed-sex sibling pairs), over-time changes in older sibling delinquency were related to younger sibling delinquency two years later as well as the change pattern in younger sibling delinquency over time. Strengths, limitations and possible implications for research and intervention of adolescent delinquency are discussed. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Treatment of atypical autism in Martin-Bell syndrome

The paper reports the case of sibs, brother and sister, with Martin-Bell's syndrome confirmed cytogenetically. Mental retardation and autism were the main phenomena in the clinical picture. Positive effect was achieved by means of Skvortsov--Osipenko method (metameric injection of cerebral hydrolysates' preparations, stimulation of visual, acoustic and proprioceptive analyzers). A decline of the signs of intellectual retardation and autism were observed in both children.     

Pseudometabolic expression and phenotypic variability of calpain deficiency in two siblings

Two siblings originating from Reunion Island were affected by a limb-girdle muscular dystrophy (LGMD) type 2A and carried the same two mutations in the calpain gene: 946-1 AG-->AA, affecting a splice site, and S744G. They demonstrated the clinical variability possible with calpain-3 mutations. Onset was around 20 years of age in each of them. The girl's symptoms mimicked a metabolic myopathy, while her brother, at the same age, presented a classical phenotype of LGMD in an advanced functional stage.     

Deletion mapping by FISH with BACs in patients with partial monosomy 22q13

We describe three siblings with hyperparathyroidism due to multiple parathyroid adenomas without evidence of other endocrinological abnormalities. A 22-year-old woman had two parathyroid adenomas complicated by multiple ossifying jaw fibromas. Her sister, aged 29, also suffered from primary hyperparathyroidism associated with two parathyroid adenomas one of which was also suspected to be a carcinoma. These two female patients had unusual multiple small uterine polyps, which were diagnosed as adenomyomatous polyps. Their brother, aged 17, had two parathyroid adenomas complicated by urolithiasis. These three patients are characterized by young adult-onset familial isolated hyperparathyroidism due to multiple adenomas with various complications including ossifying jaw fibroma and uterine adenomyomatous polyps. These clinical features are different from those of familial hyperparathyroidism associated with multiple endocrine neoplasia.     

Major differences in response to graded hypoxia between hypoglossal and neocortical neurons

Allogeneic T cells are capable of discriminating between leukemia cells and non-malignant hematopoetic cells. This has been concluded from clinical BMT data and demonstrated by in vitro experiments. We analyzed the frequency and specificity of leukemia-reactive T cells from syngeneic and allogeneic blood donors by limiting dilution assays for interleukin-2-producing (TH1) and cytotoxic (CTLp) T cells. Target cells were leukemia blasts obtained from a patient with common ALL. Control targets were generated by EBV transformation. Effector cells were generated from the peripheral blood of the patient in remission, from his syngeneic brother and from eight healthy, HLA-mismatched volunteers. The effector cells were stimulated with leukemia cells and interleukin-2. Neither the patient nor his brother were able to generate anti-leukemic CTLp or TH1. The HLA-mismatched allogeneic donors displayed anti-leukemic CTLp frequencies with a range from 0 to 68 million. TH1 cells with anti-leukemic specificity were not detectable. We conclude that there are great inter-individual differences in the GVL potential of fully allogeneic peripheral T lymphocytes. It is possible to identify T cell lines with reactivity against leukemia blasts and non-reactivity against normal hematological cells from the same individual. These cell lines are potential effector cells for immunotherapy of human leukemia.     

Protein sizes and stoichiometry in the chaperone SecB--RBPTI complex estimated by ANS fluorescence

Two unrelated patients of Pakistani origin presented with primary hyperoxaluria type 1 (PH1) at 4 months and 3 years of age, respectively. While the younger patient failed to thrive and suffered from early renal failure, the older one showed a relatively benign history with urolithiasis as the main feature of the disease. In both patients the diagnosis was confirmed by assessment of alanine:glyoxylate aminotransferase catalytic and immunoreactivity in liver biopsy specimens. The underlying genetic defect was found to be a combined deletion and insertion in exon 8 which alters the reading frame of the protein. The nucleotide change introduces a Stu1 restriction site which facilitated typing of additional family members. Both patients and a further affected brother were homozygous for this mutation, while their parents were heterozygous for it. This mutation is the first deletion/insertion identified in PH1. Although rare in our PH1 patient cohort (2.5% of alleles), the finding of 2 homozygous apparently unrelated individuals of the same ethnic origin suggests that it may prove worthwhile to screen other Asian patients for this mutation. These PH1 cases present further evidence that factors other than genotype contribute significantly to the clinical presentation and severity of PH1.     

Kindler syndrome. Clinical and ultrastructural findings

BACKGROUND: Kindler syndrome is a genodermatosis that combines clinical features of hereditary epidermolysis bullosa and poikiloderma congenitale. The ultrastructural level of blister formation has not been well characterized. OBSERVATIONS: Two brothers with Kindler syndrome had a history of primarily acral blistering since infancy as well as photosensitivity. Blister formation was found through the basal layer. Marked tonofilament clumping was found in intact keratinocytes adjacent to the blisters. The younger brother (aged 21 years) had actinic keratoses, which have not been previously described in Kindler syndrome. CONCLUSIONS: The findings of basal layer separation in both spontaneous and induced blisters in Kindler syndrome suggest this is the true level of blister formation. The finding of actinic keratoses in a young patient with Kindler syndrome suggests that some patients may be at increased risk for early solar-induced skin disease. The presence of clumped tonofilaments in keratinocytes adjacent to blistered areas suggests an abnormality of keratin 5 or 14 could be present and may play a role in blister formation in patients with Kindler syndrome.     

Play psychotherapy of a profoundly incest abused boy: A Jungian approach.

A Jungian play psychotherapy approach to the treatment of a profoundly sexually abused mother–son incest victim is described. The S started treatment at the age of 4.5 yrs. He and his older brother had been initially raised by their young single mother who supported herself by working as a prostitute. The S's mother had displayed severe parenting deficits including neglect of both children, leaving the children alone for up to 3 days, physical abuse of the S's older brother, and sexual abuse of the S. The S and his brother were taken into temporary care for the 1st time when the S was 4 mo old. The S was formally adopted when he was 37 mo old. Emphasis is placed on (1) the therapeutic alliance; (2) a teleological approach, that is, following the child's play as it unfolds; and(3) the differences between acting-out and acting-in. The play during therapy evolved through several stages: symbolic and verbal disclosure in the 1st session; terror and rage; sexual, urination, cleansing, and nurturant themes; ego and superego development; and latency aged play. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Treatment with CL 316,243, a beta 3-adrenoceptor agonist, reduces serum leptin in rats with diet- or aging-associated obesity, but not in Zucker rats with genetic (fa/fa) obesity

Discrete subaortic stenosis (DSS) accounts for 8 to 20% of all cases of congenital left ventricular outflow tract obstruction. There have been few scattered reports of left ventricular obstructive lesions occurring in immediate family members of patients with DSS. This is a report of four cases of DSS in one family: one brother with a fibrous ring, and two sisters and the son of one of the sisters with a fibrous membrane. The occurrence of multiple cases of DSS in this family suggests an autosomal dominant mode of inheritance.     

Rapid detection of engraftment using T cell receptor gene polymorphism after allogeneic bone marrow transplantation in an alloimmunized child with severe aplastic anemia

A severely alloimmunized boy with aplastic anemia received an HLA-identical BMT from his brother. Despite intensive immunosuppression and large marrow dose, peripheral signs of engraftment occurred only late under G-CSF treatment. With leukocyte counts of < 0.5 x 10(9)/l, chimerism could be proven not only by oligonucleotide fingerprinting but also within 48 h by analysis of polymorphism in the TCR gene family. This rapid and sensitive method to detect engraftment before it became quantitatively evident was important for the clinical management of the patient, obviating the need to search for an alternative marrow donor.     

Diode laser cyclophotocoagulation: histopathology in two cases of clinical failure

We report an unusual case of a 55 year old Japanese woman with a seminoma but relatively normal menses. The patient was a phenotypic female with late onset menarche (18 years of age), who was amenorrhoeic for the first year, followed by menses of one to three days' slight flow with dysmenorrhoea, but an otherwise normal menstrual history. A typical seminoma was removed from the left adnexal region and an immature testis was identified separately as an associated right adnexal mass. Repeated karyotypic studies on peripheral blood lymphocyte cultures showed only 46,X,-Y,t(Y;15)(q12;p13). Cytogenetic examination of the patient's younger brother, who had fathered three healthy children, showed an identical karyotype. Mosaicism of 46,X,-Y,t(Y;15)(q12;p13)/45,X cell lines was found in skin samples from the patient's elbow and genital regions, although there were no clinical stigmata of Turner syndrome. An androgen receptor binding assay of cultured genital skin fibroblasts was negative. Molecular analysis using Southern blot hybridisation, PCR, and direct DNA sequencing showed that neither the patient nor her brother had a detectable deletion or other abnormalities of Y chromosome sequences, including the SRY (sex determining region of the Y chromosome) gene sequence. These findings suggest that Turner mosaicism of the 45,X cell line may have contributed to this atypical presentation in an XY female, although we cannot exclude abnormalities of other genes related to sex differentiation.