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.

Is Sanfilippo type B in your mind when you see adults with mental retardation and behavioral problems?

Sanfilippo type B is an autosomal recessive mucopolysaccharidosis (MPS IIIB) caused by deficiency of N-acetyl-alpha-D-glucosaminidase, a lysosomal enzyme involved in the degradation of heparan sulfate. It is characterized by neurologic degeneration, behavioral problems, and mental decline. Somatic features are relatively mild and patients with this disorder can reach late adulthood. It is the most common subtype of MPS in the Netherlands and probably underdiagnosed in adult persons with mental retardation (MR). In order to increase knowledge on the adult phenotype and natural history in Sanfilippo type B, we present the clinical data of 20 patients with this disorder. Sixteen of them were followed for one to three decades. Six died between 28 and 69 years of age, mainly from pneumonia and cachexia; the surviving patients were 18-63 years old. Apart from the youngest, they had lost mobility at 36-68 years. Most had developed physical problems, in particular in the 4th-6th decade of life: cardiac disease (cardiomyopathy, atrial fibrillations), arthritis, skin blistering, swallowing difficulties requiring feeding by a gastrostomy tube, and seizures. The course of the disease was dominated in most of them by challenging behavioral problems with restlessness, extreme screaming and hitting, difficult to prevent or to treat pharmaceutically. Even in absence of knowledge of the history of an elderly patient with MR, the presence of behavioral problems should prompt metabolic investigation for MPS.

The endocrine system in treated patients with classical galactosemia.

Endocrine abnormalities in classical galactosemia, female hypergonadotropic hypogonadism and low thyroxin in neonates, have been reported. Galactosemia is a secondary glycosylation disorder and hypoglycosylation of glycoproteins has a role in this dysfunction. Hypoglycosylation, improves but does not completely disappear with dietary treatment. Our aim was to evaluate the endocrine system in treated patients (n = 37, 25 females, 12 males, age 5-19 years). Endocrine determinations were compared to age and gender matched reference ranges. Sample t-test (to test differences with reference population) and linear regression analysis between hGH (growth hormone), IGF-1 (insulin-like growth factor), IGFBP-3 (insulin growth factor binding protein), FSH (follicle stimulating hormone), LH (luteinizing hormone) and GALT activity, and soy intake, was carried out. Mean IGF-1 Z-score was -0.98 +/- 0.84 (range -2.59 to 1.21) (P < 0.001) in females and 0.03 +/- 0.55 (range -1.0 to 0.89) (P = 0.84) in males. Mean IGFBP-3 Z-score was -0.98 +/- 1.3 (range -3.0 to 2.0) (P < 0.001) in females and 0.26 +/- 0.93 (range -0.94 to 2.0) (P = 0.35) in males. IGF-1 and IGFBP-3 were positively correlated (P < 0.001). IGF-1 or IGFBP-3 Z-scores and age, hGH, estradiol, GALT activity or soy intake were not correlated. FSH was elevated in females, other axes were normal. Besides the hypergonadotropic hypogonadism in females, IGF-1 and IGFBP-3 are in the low to normal ranges in girls. Hypoglycosylation in galactosemia is diet dependent and could worsen when galactose intake increases either because of poor compliance or diet liberalization.

Effect of calcium, vitamins K1 and D3 on bone in galactosemia.

Classical galactosemia is an inherited disorder of galactose metabolism. Recently, diminished bone mineral content (BMC) in children and adolescents has been found. The aim of this study was to evaluate the effect of calcium, vitamins K(1) and D(3) supplementation on bone in children with galactosemia. A 2-year randomized, double-blind, placebo-controlled clinical trial was undertaken in which 40 children with classical galactosemia (13 males and 27 females, aged 3-17 years) were included to receive daily either 750 mg calcium, 1.0 mg vitamin K(1) and 10.0 microg vitamin D(3) or placebo. BMC of femoral neck, lumbar spine and total body and body composition data were determined by dual energy X-ray absorptiometry (DXA) at baseline and after 1 and 2 years. Diet was assessed using a food frequency questionnaire and a 3-day food diary. Biochemical measurements were determined at baseline and after 1 and 2 years. In the children receiving treatment, carboxylated osteocalcin (cOC) concentration significantly increased (P < 0.001) and undercarboxylated osteocalcin (ucOC) concentration significantly decreased (P = 0.001) when compared to the children receiving placebo. Furthermore, there was a statistically significant increase in BMC of lumbar spine (P = 0.001), lean tissue mass (LTM: P = 0.016) and fat mass (FM: P = 0.014) in the treatment group when compared to the placebo group. The significant increase in cOC and decrease in ucOC concentration in the treatment group were present in prepubertal (P < 0.001 and P = 0.006 respectively) and pubertal children (P = 0.004 and P = 0.042 respectively). The significant increase in BMC of lumbar spine in the treatment group was present only in the prepubertal children (P = 0.015). Supplementation of calcium, vitamins K(1) and D(3) given in this dose (750 mg, 1.0 mg and 10.0 mug respectively) is likely to have a role in the treatment of BMC abnormalities in galactosemia.

Untreated classical galactosemia patient with mild phenotype.

Despite life-long galactose restriction, long-term complications generally occur in classical galactosemia. We report an adult male with classical galactosemia (Q188R homozygosity, severely reduced erythrocyte galactose-1-phosphate uridyltransferase activity) who has a surprisingly mild phenotype despite genotype and enzyme activity associated with severe phenotype. Moreover he has a normal galactose intake from the age of 3 years. This case is probably an example of the important role of yet unknown susceptibility and or modifier genes.

Mutation of the COG complex subunit gene COG7 causes a lethal congenital disorder.

The congenital disorders of glycosylation (CDG) are characterized by defects in N-linked glycan biosynthesis that result from mutations in genes encoding proteins directly involved in the glycosylation pathway. Here we describe two siblings with a fatal form of CDG caused by a mutation in the gene encoding COG-7, a subunit of the conserved oligomeric Golgi (COG) complex. The mutation impairs integrity of the COG complex and alters Golgi trafficking, resulting in disruption of multiple glycosylation pathways. These cases represent a new type of CDG in which the molecular defect lies in a protein that affects the trafficking and function of the glycosylation machinery.

Tetrahydrobiopterin-responsive phenylalanine hydroxylase deficiency, state of the art.

Since 1999 an increasing number of patients with phenylalanine hydroxylase (PAH) deficiency are reported to be able to decrease their plasma phenylalanine (Phe) concentrations after a 6R-tetrahydrobiopterin (BH(4)) challenge. The majority of these patients have mild PKU or MHP (mild hyperphenylalaninemia) and harbour at least one missense mutation in the PAH gene associated with this phenotype. The rate of decrease and the lowest achieved Phe level vary between patients with different genotypes but appears to be similar in patients with the same genotype. A number of the mutations associated with BH(4)-responsiveness have been studied in an 'in vitro' eukaryotic cell expression system leading to biosynthesis of a mutant PAH enzyme with some residual activity. Patients bearing mutations that cause severe structural distortion in the expressed protein (loss of function mutations), leading to undetectable PAH activity, are not responsive to BH(4). These observations suggest that residual PAH activity (in vitro) is a prerequisite for BH(4)-responsiveness. However, an in vitro residual PAH activity is not a guarantee for in vivo BH(4)-responsiveness. Mechanisms behind this responsiveness could be relieve of decreased binding affinity for BH(4), BH(4)-mediated increase of PAH gene expression or stabilization of the mutant enzyme protein by BH(4). BH(4)-responsive PAH-deficient patients have only been reported since 1999. For the western countries this is explained by the fact that the manufacturer changed the diastereoisomeric purity of the BH4 preparation from 69% of the natural 6R-BH4 (31% of 6S-BH4) to 99.5% 6R-BH4. The new findings on BH(4)-responsiveness may be of clinical relevance because these patients can be treated with BH(4) with concomitant relief or withdrawal of the burdensome PKU diet. These observations warrant further clinical studies to assess efficacy, optimal dosage, and safety of BH(4) treatment in this group. The data strongly emphasize the necessity of the BH(4) loading test in patients detected in the newborn PKU screening.