Tyrosinemia type 1 and Angelman syndrome due to paternal uniparental isodisomy 15.

Uniparental isodisomy arises when an individual inherits two copies of a specific chromosome from a single parent, which can unmask a recessive mutation or cause a problem of genetic imprinting. Here we describe an exceptional case in which the patient simultaneously presents tyrosinemia type 1 and Angelman syndrome. The genetic studies showed that the patient presents paternal uniparental isodisomy of chromosome 15, with absence of the maternal homolog. As a consequence of this isodisomy, the patient is homozygous for the mutation IVS12+5G>A in the FAH gene, located in the chromosomal region 15q23-25, causing tyrosinemia type 1. The mutation was inherited from his father in double dosage, whereas the mother is not a carrier, which implies that the recurrence risk in the family is negligible. On the other hand, the lack of maternal contribution causes Angelman syndrome, a neurodevelopmental disorder associated with a loss of maternal gene expression in chromosome region 15q11-q13, and more specifically, of the UBE3A gene. This gene shows a tissue-specific imprinting, and only the maternally derived allele is expressed in certain areas of the brain. We observed through a literature review that uniparental disomy probably occurs more frequently than suspected, although it is more usually detected when the uniparental disomy implies the appearance of a disease because of the gene imprinting or by reduction to homozygosity of a recessive mutation. The conclusion is that uniparental disomy should always be considered when more than one genetic disease mapping to the same chromosome is present in a patient.

Brain injury in glutaric aciduria type I: the value of functional techniques in magnetic resonance imaging.

BACKGROUND: Acute striatal necrosis is a devastating consequence of encephalopathic crisis in patients with glutaric aciduria type I (GA-I), but the mechanisms underlying brain injury are not completely understood. OBJECTIVE: To approach pathophysiological aspects of brain injury in GA-I by means of functional techniques in magnetic resonance imaging (MRI). PATIENTS AND METHODS: Four patients during an acute encephalopathic crisis and three asymptomatic siblings with GA-I underwent single-voxel hydrogen magnetic resonance spectroscopy (MRS) and brain MRI including gradient echo T1-weighted, FLAIR, T2-weighted and diffusion-weighted imaging. RESULTS: The study was performed between three and eight days after the onset of acute encephalopathic crisis. Isotropic diffusion images showed high signal changes with corresponding low apparent diffusion coefficient values within the putamen, caudate nuclei and globus pallidus (four patients), and the cerebral peduncles including the substantia nigra (one patient). The study disclosed normal findings in asymptomatic siblings. MRS showed decreased N-acetyl-aspartate/creatine ratio at the basal ganglia in encephalopathic patients when compared to a group of sex- and age-matched controls. CONCLUSIONS: Brain injury in GA-I is characterized by the presence of cytotoxic edema and reduced neuronal integrity by functional imaging techniques. Involvement of the basal ganglia may be asymmetrical in patients with unilateral motor disorder and may extent to the cerebral peduncles and substantia nigra, which may be responsible for the acute onset dystonia in some patients. Functional techniques failed to demonstrate any abnormalities in asymptomatic patients, which is in agreement with the integrity of basal ganglia structures observed by conventional MRI sequences.