Clinical and molecular characterization of an extended family with Fabry disease.

OBJECTIVE: To characterize clinical manifestations, biochemical changes, mutation of alpha-Galactosidase (alpha-Gal A) gene A (GLA), and functional capability of mutant protein. MATERIAL AND METHOD: Seventeen subjects from a family with a newly diagnosed patient with Fabry disease were enrolled in the present study. In each individual, clinical history, physical examination, leukocyte enzyme activity of alpha-Gal A, and mutation analysis were performed. Those with a mutation were further investigated by ophthalmological and audiological evaluations, electrocardiography, echocardiogram, urinalysis, and blood tests to determine renal insufficiency. Expression study of the mutant protein was performed using a Pichia pastoris expression system. RESULTS: Four affected males and five symptomatic female carriers were identified. Clinical manifestations included severe neuropathic pain, acroparesthesia, hypo-/hyper-hidrosis, frequent syncope, ischemic stroke, cardiac hypertrophy, corneal dystrophy and cart-wheel cataract, high frequency sensorineural hearing loss, periorbital edema and subcutaneous edema over hands and interphalangeal joints. None had angiokeratoma or renal symptoms. The authors identified a novel mutation, p.L106R, in the GLA gene. Recombinant expression of the mutant protein gave little or no enzyme activity compared to the normal protein. CONCLUSION: There were intrafamilial clinical variabilities, but consistent findings of the absence of angiokeratoma and renal symptoms, which could represent a unique feature of this particular mutation.

Thanatophoric dysplasia: roentgenographic findings and detection of a de novo mutation of FGFR3 gene in a Thai patient.

Thanatophoric dysplasia is the most common neonatal lethal skeletal dysplasia with an estimated incidence of 1 in 20,000 live births. This condition shares some similarity of radiological findings with other types of lethal skeletal dysplasias. Definite diagnosis is necessary for accurate medical and genetic counseling. The authors describe a male neonate who had characteristic features of thanatophoric dysplasia type I including severe shortening of limbs with redundant skin folds, large head, frontal bossing, depressed nasal bridge, and narrow thoracic cage with severe respiratory insufficiency. Postmortem radiographs revealed short ribs, flat vertebral bodies (platyspondyly), hypoplastic iliac bones, marked shortening of long bones including short and mild bowing of both femora, oval radiolucent area of proximal femur. Molecular analysis of Fibroblast Growth Factor Receptor 3 (FGFR3) gene identified a de novo mutation, p.R248C, in exon 7.

Nonketotic hyperglycinemia in two siblings with neonatal seizures.

Seizures are a common problem in neonates. Differential diagnoses include infection, trauma, hypoxia and congenital metabolic disorders. Among these, congenital metabolic disorder is less familiar to general pediatricians. We report two patients with nonketotic hyperglycinemia (NKH), a rare and lethal congenital metabolic disease. Transient hyperammonemia and transient hypouricemia, uncommon features found in NKH, were detected in one patient. High doses of sodium benzoate and dextromethorphan failed to modify the clinical course. Neuropathology denoted characteristic diffuse vacuolization and changes in reactive and gliotic astrocytes. The clinical course, biochemical findings, diagnostic approaches and diagnostic tests are discussed in detail. Recent modalities of treatment are reviewed. Because of its rarity and rapidly progressive course, it maybe underdiagnosed resulting in death before being recognized. Awareness of the possibility of congenital metabolic disorder in early neonatal catastrophe will increase the diagnostic rate.

Isolated lissencephaly sequence with contiguous gene deletion detected by FISH analysis: a case report.

BACKGROUND: Lissencephaly is a clinically and genetically heterogeneous malformation of the brain, usually leading to a severe disabling condition and seizures. The recent discovery of molecular techniques and identification of lissencephaly genes (e.g. LISI and DCX) has allowed etiologic diagnosis of this disorder feasible. OBJECTIVE: To describe a patient with lissencephaly in whom fluorescence in situ hybridization (FISH) determined etiologic diagnosis, providing precise genetic counseling and possible prenatal diagnosis for the family. CLINICAL REPORT AND STUDY RESULTS: The authors report a 4 month-old girl who presented with intractable, generalized myoclonic seizures at I month of age. The patient was born at 37 weeks' gestation, to a G4P1A2 36-year-old woman. Chromosome analysis from amniotic fluid performed for advanced maternal age revealed normal karyotype. Pregnancy was complicated by polyhydramnios. Computed tomographic scan of the brain at age one month showed a total absence of gyral formation. FISH of the metaphase chromosome from the patient, using Smith-Magenis and Miller-Dieker/ILS probe showed two signals of Smith-Magenis probe but only one signal of Miller-Dieker/ILS probe, indicating a microdeletion of 17pl3.3 region including LIS1 gene. Hybridization of the ILS probe on the metaphase chromosome of both parents was normal. CONCLUSION: A confirmation of contiguous gene deletion in this patient lead to an etiologic diagnosis of lissencephaly. This information allowed precise genetic counseling, estimation of recurrent risk, and definite prenatal diagnosis available to the family. The authors suggest FISH 17p13.3 studies be performed in addition to a standard metaphase analysis in all patients with type I lissencephaly.