Hagit Baris

Human TUBB3 Mutations Perturb Microtubule Dynamics, Kinesin Interactions, and Axon Guidance

We report that eight heterozygous missense mutations in TUBB3, encoding the neuron-specific beta-tubulin isotype III, result in a spectrum of human nervous system disorders that we now call the TUBB3 syndromes. Each mutation causes the ocular motility disorder CFEOM3, whereas some also result in intellectual and behavioral impairments, facial paralysis, and/or later-onset axonal sensorimotor polyneuropathy. Neuroimaging reveals a spectrum of abnormalities including hypoplasia of oculomotor nerves and dysgenesis of the corpus callosum, anterior commissure, and corticospinal tracts. A knock-in disease mouse model reveals axon guidance defects without evidence of cortical cell migration abnormalities. We show that the disease-associated mutations can impair tubulin heterodimer formation in vitro, although folded mutant heterodimers can still polymerize into microtubules. Modeling each mutation in yeast tubulin demonstrates that all alter dynamic instability whereas a subset disrupts the interaction of microtubules with kinesin motors. These findings demonstrate that normal TUBB3 is required for axon guidance and maintenance in mammals.

The spectrum of vascular anomalies in patients with PTEN mutations: implications for diagnosis and management

Background: Mutations in the PTEN gene cause two disorders that predispose to cancer, Bannayan–Riley–Ruvalcaba and Cowden syndromes. Some patients with a PTEN mutation have only macrocephaly and autism, but they may still be at risk for neoplasms. Vascular anomalies occur in patients with a PTEN mutation, but they have not been systematically studied or precisely defined. Method: We analysed the clinical and radiological features of the vascular anomalies in 26 patients with PTEN mutations who were either seen or had their medical records reviewed at Children’s Hospital Boston. Results: All 23 patients who had their head circumference measured were macrocephalic, and all 13 male patients who were fully examined had penile freckling. Vascular anomalies were found in 14/26 (54%) of patients: 8/14 (57%) had multiple lesions and 11/13 (85%) who had cross-sectional imaging had intramuscular vascular lesions. Radiographic studies showed that 12/14 (86%) were fast-flow vascular anomalies, and angiography typically showed focal segmental dilatation of draining veins. Excessive ectopic fat in the vascular anomalies was present in 11/12 (92%) of patients on CT or MRI. Intracranial developmental venous anomalies (DVAs) were found in 8/9 (89%) of patients who had brain MRI with contrast. Conclusions: Vascular anomalies in patients with a PTEN mutation are typically multifocal intramuscular combinations of fast-flow channels and ectopic fat. Cerebral DVAs are very common. PTEN mutational analysis should be considered for all macrocephalic patients with fast-flow vascular anomalies or multiple intracranial DVAs.

Isolated sulfite oxidase deficiency: a case report with a novel mutation and review of the literature.

Isolated sulfite oxidase deficiency is a rare but devastating neurologic disease that usually presents in early infancy with seizures and alterations in muscle tone. Only 21 cases have been reported in the literature. We report a case of a newborn infant boy with isolated sulfite oxidase deficiency who presented with generalized seizures on his fourth day of life. Plasma total homocysteine was not detectable. Urinary sulfite, thiosulfate, and S-sulfocysteine levels were elevated. The patient began a low-methionine and low-cysteine diet and was treated with thiamine and dextromethorphan. However, he became increasingly microcephalic and was severely developmentally delayed. Mutation analysis of the sulfite oxidase gene revealed that the patient was homozygous for a novel 4-base pair deletion, and both of his parents were found to be heterozygous carriers of the same deletion. We reviewed the clinical, biochemical, neuroradiologic, and neuropathologic features in all published cases of isolated sulfite oxidase deficiency. Seizures or abnormal movements were prominent features in all cases. Developmental delays were reported in 17 cases. Ectopia lentis was detected in 9 cases. Clinical improvement with dietary therapy was seen in only 2 patients, both of whom presented after the age of 6 months and had relatively mild developmental delays. Plasma or urinary S-sulfocysteine levels were elevated in all cases. Urinary sulfite was detected in all except 1 case. Cerebral atrophy and cystic encephalomalacia were observed with neuroradiologic imaging and were noted in all 3 postmortem reports of isolated sulfite oxidase deficiency. The main alternative in the differential diagnosis of isolated sulfite oxidase deficiency is molybdenum cofactor deficiency.

Diagnostic utility of array-based comparative genomic hybridization in a clinical setting.

Array‐based comparative genomic hybridization is a recently introduced technique for the detection of submicroscopic genomic imbalances (deletions or duplications) across the entire genome. To assess the potential utility of a widely available array‐based comparative genomic hybridization platform that targets specific, clinically relevant, loci across the genome for cytogenetic diagnosis in a clinical setting, we reviewed the medical records of all 373 patients at Childrens Hospital Boston who had normal chromosomal analysis and were tested with this targeted array‐based comparative genomic hybridization over a 1‐year period from November 1, 2004 to October 31, 2005. These patients were tested because of a suspicion of chromosomal abnormalities based on their clinical presentation. Thirty‐six patients (9.7%) had abnormal array‐based comparative genomic hybridization results. Twenty patients (5.4%) had potentially pathogenetic genomic imbalances and 16 patients (4.3%) had copy number variations that are not believed to be pathogenetic. Thirteen of 234 patients (5.6%) with mental retardation/global developmental delay, 10/114 patients (8.8%) with facial dysmorphism, 5/58 patients (8.6%) with multiple congenital anomalies, and 4/35 patients (11.4%) with both facial dysmorphism and multiple congenital anomalies had potentially pathogenetic genomic imbalances. Targeted array‐based comparative genomic hybridization is a clinically available test that is useful in the evaluation of patients suspected of having chromosomal disorders. However, it is best used as an adjunct to chromosomal analysis when a clear genetic diagnosis is unavailable.

Cockayne syndrome: The developing phenotype

Cockayne syndrome is a rare autosomal recessive condition comprising microcephaly, “cachectic dwarfism” and progressive neurological degeneration. We present a 21‐year‐old woman who was not diagnosed with Cockayne syndrome type I until she was 21 years old. Family photographs demonstrated that the phenotype of Cockayne syndrome did not become evident until she was 8 years old. She had severe microcephaly, micrognathia, protruding ears, dental overcrowding with caries, progressive spastic quadriparesis, and severe developmental regression. Her head computed tomography (CT) showed bilateral calcification of the globus pallidus and global atrophy. The purpose of this clinical report is to alert clinicians to the fact that the phenotypic features of Cockayne syndrome may be very subtle early in the course of the disease.

A germline or de novo mutation in two families with Gaucher disease: implications for recessive disorders

Gaucher disease (GD) is an autosomal recessive storage disorder that most commonly results from the inheritance of one identifiable mutant glucocerebrosidase (GBA1) allele from each parent. Here, we report two cases of type 2 GD resulting from the inheritance of one identifiable paternal mutant allele and one allele that likely resulted from a maternal germline mutation. Germline mutations or mosiacism are not generally associated with autosomal recessive disorders. The probands from the two unrelated families had the same maternal mutation, leu444pro, that we propose resulted from a de novo maternal germline mutation occurring at this known ‘hotspot’ for mutation. This first report of a germline mutation for a common point mutation leu444pro (c.1448 T>C;p.leu483pro) in GD has significant implications for molecular diagnostics and genetic counseling in recessive disorders.

Identification of a novel polymorphism : The duplication of the NPHP1 (Nephronophthisis 1) gene

Hagit Baris, Bassem A. Bejjani, Wen-Hann Tan, David L. Coulter, Judith A. Martin, Andrea L. Storm, Barbara K. Burton, Sulagna C. Saitta, Marzena Gajecka, Blake C. Ballif, Mira B. Irons, Lisa G. Shaffer, and Virginia E. Kimonis* Division of Genetics, Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts Signature Genomic Laboratories, LLC, Spokane, Washington Health Research and Education Center, Washington State University, Spokane, Washington Department of Neurology, Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts Inland Northwest Genetics Clinic, Spokane, Washington Department of Medical Genetics and Metabolism, Children’s Hospital Central California, Madera, California Division of Genetics and Department of Pediatrics, Children’s Memorial Hospital and Northwestern University Feinberg School of Medicine, Chicago, Illinois Division of Human Genetics, The Children’s Hospital of Philadelphia and University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Krabbe disease : Severe neonatal presentation with a family history of multiple sclerosis

Krabbe disease, also known as globoid cell leukodystrophy, is a rare autosomal recessive disorder caused by a deficiency of a lysosomal enzyme, galactocerebrosidase. This defect prevents normal turnover of the galactolipids and results in progressive demyelination. In the infantile form, symptoms typically present at 3 to 6 months of age with subsequent neurologic deterioration. We report a case with presentation on day 7 of life and rapid progression culminating in death at 10 weeks. Galactocerebrosidase activity was absent in the leukocytes, and a 30 kb deletion in the GALC gene was found. To our knowledge, this is the earliest reported death from Krabbe disease. Several family members have multiple sclerosis, which is also a demyelinating disorder. We propose that the neonatal expression could be an example of complementary gene interaction in which coinheritance of a predisposition to multiple sclerosis led to the unusual early manifestation and rapid course of Krabbe disease in this infant. (J Child Neurol 2005;20:826—828).

Hypothelia, syndactyly, and ear malformation--a variant of the scalp-ear-nipple syndrome?: Case report and review of the literature.

The scalp‐ear‐nipple syndrome is a rare autosomal dominant condition that involves lesions of the scalp, malformed external ears, and absence of rudimentary nipples and breasts. We report a case of a woman with hypothelia, bilateral mildly malformed ears, and syndactyly of the hands and feet, and review the literature on the hypothelia/athelia phenotype. This case may represent a mild phenotype of the scalp‐ear‐nipple syndrome or a newly recognized entity.

13,845 home therapy infusions with velaglucerase alfa exemplify safety of velaglucerase alfa and increased compliance to every-other-week intravenous enzyme replacement therapy for Gaucher disease.

BACKGROUND Lifelong intravenous (IV) enzyme replacement therapy (ERT) every other week for Gaucher disease is appreciated as decreasing quality of life in a palpable way. OBJECTIVE To review the Israeli experience with the home therapy option for IV velaglucerase alfa (Shire, Lexington MA USA) infusions every-other-week in the clinical trial context, in the early access program (EAP) during a shortage with the standard commercial ERT, and currently with the commercially available drug (VPRIV, Shire). RESULTS Among 24 patients participating in trials, 1654 infusions were at home; in the EAP and commercial setting, 12,191 infusions were performed at home for a total of 154 patients with 98.4% compliance. There were no incidents of serious adverse events. CONCLUSION This is the first review of experience of 174 patients and 13,845 intravenous infusions of velaglucerase alfa for Gaucher in the home setting, underscoring its safety.