Estela Rubio-Gozalbo

The adult galactosemic phenotype

BackgroundClassic galactosemia is an autosomal recessive disorder due to galactose-1-phosphate uridyltransferase (GALT) deficiency. Newborn screening and early treatment do not completely prevent tremor, speech deficits, and diminished IQ in both sexes and premature ovarian insufficiency (POI) in women. Data on how individuals with galactosemia fare as adults will improve our ability to predict disease progression.MethodsThirty-three adults (mean age = 32.6 ± 11.7 years; range = 18–59) with classic galactosemia, confirmed by genotype and undetectable GALT enzyme activity, were evaluated. Analyses assessed associations among age, genotype, clinical features and laboratory measures.ResultsThe sample included 17 men and 16 women. Subjects exhibited cataracts (21%), low bone density (24%), tremor (46%), ataxia (15%), dysarthria (24%), and apraxia of speech (9%). Subjects reported depression (39%) and anxiety (67%). Mean full scale IQ was 88 ± 20, (range = 55–122). All subjects followed a dairy-free diet and 75–80% reported low intake of calcium and vitamin D. Mean height, weight and body mass were within established norms. All female subjects had been diagnosed with POI. One woman and two men had had children. Logistic regression analyses revealed no associations between age, genotype or gender with IQ, tremor, ataxia, dysarthria, apraxia of speech or anxiety. Each 10- year increment of age was associated with a twofold increase in odds of depression.ConclusionsTaken together, these data do not support the hypothesis that galactosemia is a progressive neurodegenerative disease. However, greater attention to depression, anxiety, and social relationships may relieve the impact of this disorder in adults.

Ovarian function in girls and women with GALT-deficiency galactosemia

Primary or premature ovarian insufficiency (POI) is the most common long-term complication experienced by girls and women with classic galactosemia; more than 80% and perhaps more than 90% are affected despite neonatal diagnosis and careful lifelong dietary restriction of galactose. In this review we explore the complexities of timing and detection of galactosemia-associated POI and discuss potential underlying mechanisms. Finally, we offer recommendations for follow-up care with current options for intervention.

New treatment strategy for Smith-Lemli-Opitz syndrome

1222 Vol 349 • April 26, 1997 1 Young TK, Moffatt MEK, O’Neil JD. Cardiovascular di seases in a Canadian arctic population. Am J Public Health 1993; 83: 881–87. 2 Frosst P, Blom HJ, Milos R, et al. A candidate gene tic risk factor for vascular disease: a common mutation in methylenetet rahydrofolate reductase. N at Genet 1995; 10: 111–13. 3 Kluijtmans LAJ, van den Heuvel LPWJ, Boers GHJ, et al. Molecular genetic analysis in mild hyperhomocysteinemia: a com mon mutation in the methylenetetrahydrofolate reductase gene is a gen etic risk factor for cardiovascular disease. Am J Hum Genet 1996; 58: 35–41. 4 Stevenson RE, Schwartz CE, Du Y-Z, Adams MJ Jr. Di fferences in methylenetetrahydrofolate reductase genotype frequen cies between blacks and whites. Am J Hum Genet 1997; 60: 229–30. 5 Moffatt ME. Current status of nutritional deficien cies in Canadian aboriginal people. Can J Physiol Pharmacol 1995; 73: 745–58.

Assessing Microstructural Substrates of White Matter Abnormalities: A Comparative Study Using DTI and NODDI.

Neurite orientation dispersion and density imaging (NODDI) enables more specific characterization of tissue microstructure by estimating neurite density (NDI) and orientation dispersion (ODI), two key contributors to fractional anisotropy (FA). The present work compared NODDI- with diffusion tensor imaging (DTI)-derived indices for investigating white matter abnormalities in a clinical sample. We assessed the added value of NODDI parameters over FA, by contrasting group differences identified by both models. Diffusion-weighted images with multiple shells were acquired in a group of 8 healthy controls and 8 patients with an inherited metabolic disease. Both standard DTI and NODDI analyses were performed. Tract based spatial statistics (TBSS) was used for group inferences, after which overlap and unique contributions across different parameters were evaluated. Results showed that group differences in NDI and ODI were complementary, and together could explain much of the FA results. Further, compared to FA analysis, NDI and ODI gave a pattern of results that was more regionally specific and were able to capture additional discriminative voxels that FA failed to identify. Finally, ODI from single-shell NODDI analysis, but not NDI, was found to reproduce the group differences from the multi-shell analysis. To conclude, by using a clinically feasible acquisition and analysis protocol, we demonstrated that NODDI is of added value to standard DTI, by revealing specific microstructural substrates to white matter changes detected with FA. As the (simpler) DTI model was more sensitive in identifying group differences, NODDI is recommended to be used complementary to DTI, thereby adding greater specificity regarding microstructural underpinnings of the differences. The finding that ODI abnormalities can be identified reliably using single-shell data may allow the retrospective analysis of standard DTI with NODDI.

Fatal cerebral edema associated with serine deficiency in CSF.

Two young girls without a notable medical history except for asthma presented with an acute toxic encephalopathy with very low serine concentrations both in plasma and cerebrospinal fluid (CSF) comparable to patients with 3-phosphoglycerate dehydrogenase (3-PGDH) deficiency. Clinical symptoms and enzyme measurement (in one patient) excluded 3-PGDH deficiency. Deficiencies in other serine biosynthesis enzymes were highly unlikely on clinical grounds. On basis of the fasting state, ketone bodies and lactate in plasma, urine and CSF, we speculate that reduced serine levels were due to its use as gluconeogenic substrate, conversion to pyruvate by brain serine racemase or decreased L-serine production because of a lack of glucose. These are the first strikingly similar cases of patients with a clear secondary serine deficiency associated with a toxic encephalopathy.