Brain function in classic galactosemia, a galactosemia network (GalNet) members review.

Classic galactosemia (CG, OMIM #230400, ORPHA: 79,239) is a hereditary disorder of galactose metabolism that, despite treatment with galactose restriction, affects brain function in 85% of the patients. Problems with cognitive function, neuropsychological/social emotional difficulties, neurological symptoms, and abnormalities in neuroimaging and electrophysiological assessments are frequently reported in this group of patients, with an enormous individual variability. In this review, we describe the role of impaired galactose metabolism on brain dysfunction based on state of the art knowledge.

Development of cancer surveillance guidelines in ataxia telangiectasia: A Delphi-based consensus survey of international experts.

Background/objectives: Ataxia telangiectasia (A-T) is a multiorgan disorder with increased vulnerability to cancer. Despite this increased cancer risk, there are no widely accepted guidelines for cancer surveillance in people affected by A-T. We aimed to understand the current international practice regarding cancer surveillance in A-T and agreed-upon approaches to develop cancer surveillance in A-T.

Metabolic Stress and Mitochondrial Dysfunction in Ataxia-Telangiectasia.

The ataxia-telangiectasia mutated (ATM) protein kinase is, as the name implies, mutated in the human genetic disorder ataxia-telangiectasia (A-T). This protein has its "finger in many pies", being responsible for the phosphorylation of many thousands of proteins in different signaling pathways in its role in protecting the cell against a variety of different forms of stress that threaten to perturb cellular homeostasis. The classical role of ATM is the protection against DNA damage, but it is evident that it also plays a key role in maintaining cell homeostasis in the face of oxidative and other forms of non-DNA damaging stress.

Fumarase deficiency in dichorionic diamniotic twins.

Fumarase deficiency is a rare autosomal recessive inborn error of metabolism of the Krebs Tricarboxylic Acid cycle. A heavy neurological disease burden is imparted by fumarase deficiency, commonly manifesting as microcephaly, dystonia, global developmental delay, seizures, and lethality in the infantile period. Heterozygous carriers also carry an increased risk of developing hereditary leiomyomatosis and renal cell carcinoma.

Mutations in SH3PXD2B cause Borrone dermato-cardio-skeletal syndrome.

Borrone Dermato-Cardio-Skeletal (BDCS) syndrome is a severe progressive autosomal recessive disorder characterized by coarse facies, thick skin, acne conglobata, dysmorphic facies, vertebral abnormalities and mitral valve prolapse. We identified a consanguineous kindred with a child clinically diagnosed with BDCS. Linkage analysis of this family (BDCS1) identified five regions homozygous by descent with a maximum LOD score of 1.

Charting a seven-year trajectory of language outcomes for a child with galactosemia.

Cross-sectional methodologies have revealed age-related deterioration in cognitive performance, reflecting progressive neurodegenerative change in a minority of children and adolescents with classic galactosemia (GAL). The application of longitudinal methodologies sensitive to age-related changes at the individual level is needed to determine the extent of any possible decline in function in children with GAL. The authors report on the developmental language outcomes of a 9-year-old female with GAL through an examination of her language development over a 7-year period using a performance tracking system based on the use of raw performance scores required for attainment at the 50th percentile for age.

Differential phonological awareness skills in children with classic galactosemia: a descriptive study of four cases.

Educational achievement, which for individuals with the metabolic disorder classic galactosemia (GAL) is significantly lower than in the wider population, correlates with self-reported quality of life. Phonological awareness skills underpin the development of literacy, and although literacy is a key contributor to successful academic outcomes, no study to date has investigated phonological awareness skills in children with GAL. This study investigated phonological awareness (PA) in four school-aged children with the disorder, two of whom were siblings.

Pre-linguistic communication skill development in an infant with a diagnosis of galactosaemia.

Background: Neonatal screening for galactosaemia (GAL) identifies the condition early, but subsequent biomedical and genetic testing fails to identify which subgroup of infants with GAL are at most risk of the language disorders associated with the condition. This study aims to present preliminary data on an infant with GAL based on assessment of pre-linguistic communication behaviours known to underpin language development.

Methods: This single case-control study profiles the pre-linguistic skills of a 13-month-old infant with GAL.

Enzyme replacement therapy and extended newborn screening for mucopolysaccharidoses: opinions of treating physicians.

We conducted a survey of physician opinions in relation to enzyme replacement therapy (ERT) and extended newborn screening (ENBS) for mucopolysaccharidoses (MPS). A questionnaire consisting of hypothetical clinical scenarios about ERT and ENBS for MPS was posted on metab-L, a list server for the metabolic community. The questionnaire included similar questions to those used in previous studies that sought the views of individuals and families affected by MPS.

Language skills in a child with Leber hereditary optic neuropathy following intrathecal chemotherapy for acute lymphoblastic leukemia.

The language skills of a male child with Leber hereditary optic neuropathy (LHON) and coincidentally treated for acute lymphoblastic leukemia (ALL) with intrathecal chemotherapy at the age of 3 years 8 months were comprehensively evaluated twice over a 6-month period approximately 5½ years after diagnosis of ALL. Despite marked chemotherapy-related leukoencephalopathic changes documented on magnetic resonance imaging, the child presented with stable language skills, which were generally average to above-average based on the normative data from a comprehensive language test battery. In light of the coincidental presentation in the child of a diagnosis of LHON, which may lead to serious vision impairment and increased vulnerability to drug neurotoxicity, coupled with a history of central nervous system (CNS)-directed treatment for ALL resulting in progressive white matter pathology, the study highlights the importance of ongoing monitoring of the child's language development throughout his adolescent years.

Galactosemia, a single gene disorder with epigenetic consequences.

Long-term outcomes of classic galactosemia (GAL) remain disappointing. It is unclear if the complications result mainly from prenatal-neonatal toxicity or persistent glycoprotein and glycolipid synthesis abnormalities. We performed gene expression profiling (T transcriptome) to characterize key-altered genes and gene clusters of four patients with GAL with variable outcomes maintained on a galactose-restricted diet, compared with controls.

Enzyme replacement therapy for mucopolysaccharidoses: opinions of patients and families.

Objectives: To assess the opinions of individuals with mucopolysaccharidoses (MPS) and their parents regarding the use of enzyme replacement therapy (ERT).

Study Design: A validated questionnaire, including hypothetical clinical scenarios about ERT for MPS, was distributed to members of MPS support groups in the United States and Australia.

Results: The questionnaire was completed by 249 MPS support group members.

Two siblings with 46,XY DSD, congenital adrenal hypoplasia, aniridia, craniofacial, and skeletal abnormalities and intrauterine growth retardation: a new syndrome?

We report on two siblings with an unusual constellation of congenital anomalies comprising 46,XY disorder of sex development (DSD), congenital adrenal hypoplasia, aniridia, dysmorphic facial features, intrauterine growth retardation, and minor skeletal abnormalities. This combination of abnormalities is yet to be recognized in the medical literature. As such, we propose that our patients represent either a new dysmorphic syndrome or a thus far unrecognized variation of a known syndrome, such as IMAGe syndrome.

Seizures, ataxia, developmental delay and the general paediatrician: glucose transporter 1 deficiency syndrome.

Aim: Glucose transporter 1 deficiency syndrome (GLUT1-DS) is an important condition for the general paediatrician's differential armamentarium. We describe a case series of eight patients in order to raise awareness of this treatable neurometabolic condition. The diagnosis of GLUT1-DS is suggested by a decreased absolute cerebrospinal fluid (CSF) glucose value (<2.