The P28T mutation in the GALK1 gene accounts for galactokinase deficiency in Roma (Gypsy) patients across Europe.

Galactokinase deficiency is an inborn error of metabolism that, if untreated, results in the development of cataracts in the first weeks of life. The disorder is rare worldwide, but has a high incidence among the Roma (Gypsies). In 1999, we reported the founder Romani mutation, P28T, identified in affected families from Bulgaria.

Novel mutations in 13 probands with galactokinase deficiency.

Galactokinase is an essential enzyme in the metabolism of galactose. Patients with deficiencies in galactokinase exhibit early-onset cataracts. We examined the sequence of the human galactokinase gene (GK1) from 13 patients exhibiting galactokinase deficiency and identified 12 novel mutations.

A founder mutation in the GK1 gene is responsible for galactokinase deficiency in Roma (Gypsies).

Galactokinase deficiency is an inborn error in the first step of galactose metabolism. Its major clinical manifestation is the development of cataracts in the first weeks of life. It has also been suggested that carriers of the deficiency are predisposed to presenile cataracts developing at age 20-50 years.

Molecular diagnosis of type 1c glycogen storage disease.

Glycogen storage disease type 1 (GSD 1) results from deficiency of the microsomal multicomponent glucose-6-phosphatase system. Malfunction of the catalytic subunit characterises GSD 1a. GSD 1b and GSD 1c are characterised by defective microsomal glucose-6-phosphate or pyrophosphate/phosphate transport, respectively.

A mutation (IVS8+0.6kbdelTC) creating a new donor splice site activates a cryptic exon in an Alu-element in intron 8 of the human beta-glucuronidase gene.

We have previously sequenced the complete coding region and the promoter region of the beta-glucuronidase gene of a patient with mild mucopolysaccharidosis type VII (MPS VII) and identified a nonsense mutation in the gene inherited from her mother. The mutation inherited from her father was not found. Here, we have extended the sequence analysis of the introns to cover all putative lariat branch points and putative intronic enhancers, although no nucleotide changes have been found in these regions.

Clinical, biochemical and molecular findings in a patient with X-linked liver glycogenosis followed for 40 years.

Unlabelled: Phosphorylase kinase (PHK) is a regulatory enzyme in glycogen metabolism. Mutations in the gene encoding the alpha subunit of PHK (PHKA2) have been shown to be responsible for X-linked liver glycogenosis (XLG). XLG, a frequent type of glycogen storage disease, is characterised by hepatomegaly and growth retardation.

Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0.

Glycogen storage disease type 0 (GSD-0) is a rare form of fasting hypoglycemia presenting in infancy or early childhood and accompanied by high blood ketones and low alanine and lactate concentrations. Although feeding relieves symptoms, it often results in postprandial hyperglycemia and hyperlactatemia. The glycogen synthase (GS) activity has been low or immeasurable in liver biopsies, whereas the liver glycogen content has been only moderately decreased.

Lysosomal enzyme activities in serum and leukocytes from patients with carbohydrate-deficient glycoprotein syndrome type IA (phosphomannomutase deficiency).

From 10 patients with carbohydrate-deficient glycoprotein (CDG) syndrome due to phosphomannomutase (PMM) deficiency, out of 10 lysosomal enzymes, 7 enzyme activities were measured in serum and 9 in leukocytes. In serum there was a 2-fold to 4-fold increase in activity of beta-glucuronidase, beta-hexosaminidase, beta-galactosidase, and arylsulphatase A. In leukocytes, however, several enzymes had reduced activity, particularly alpha-fucosidase, beta-glucuronidase and alpha-mannosidase.

Low beta-glucuronidase enzyme activity and mutations in the human beta-glucuronidase gene in mild mucopolysaccharidosis type VII, pseudodeficiency and a heterozygote.

Deficiency of beta-glucuronidase is the cause of the human lysosomal storage disorder mucopolysaccharidosis type VII (MPS VII). The wide interfamilial variation in the presentation of this disorder complicates clinical diagnosis. Since greatly reduced beta-glucuronidase enzyme activity may also be found in healthy individuals (pseudodeficiency), diagnosis based on the biochemical phenotype is also difficult.

Hypergalactosaemia in a newborn: self-limiting intrahepatic portosystemic venous shunt.

Unlabelled: Hypergalactosaemia was found in 4 day-old boy during newborn screening. He had no enzyme deficiency but an intrahepatic vascular malformation permitting significant portosystemic venous shunting. The shunt caused hyperammonaemia, accentuated after meals, alimentary hyperglycaemia and hypergalactosaemia, and excess excretion of lactic, 3-hydroxy butyric and other organic acids in urine.

Autosomal recessive liver phosphorylase kinase deficiency caused by a novel splice-site mutation in the gene encoding the liver gamma subunit (PHKG2).

To facilitate mutation analysis of patients with an autosomal recessive form of liver phosphorylase kinase deficiency, the genomic structure of the gene encoding the testis/liver gamma subunit (PHKG2) was established. The gene consist of 10 exons. The translation start site is located in exon 2.

Phenotypic and genotypic overlap between atelosteogenesis type 2 and diastrophic dysplasia.

Mutations in the diastrophic dysplasia sulfate transporter gene DTDST have been associated with a family of chondrodysplasias that comprises, in order of increasing severity, diastrophic dysplasia (DTD), atelosteogenesis type 2 (AO2), and achondrogenesis type 1B (ACG1B). To learn more about the molecular basis of DTDST chondrodysplasias and about genotype-phenotype correlations, we studied fibroblast cultures of three new patients: one with AO-2, one with DTD, and one with an intermediate phenotype (AO2/DTD). Reduced incorporation of inorganic sulfate into macromolecules was found in all three.

Mucolipidosis type II in a domestic shorthair cat.

A seven-month-old, female domestic shorthair cat was presented to the Veterinary Teaching Hospital, University of Zurich, with abnormal facial features, retarded growth and progressive hindlimb paresis. On physical examination the cat had a flat, broad face with hypertelorism, frontal bossing, small ears and thickened upper and lower eyelids. The corneas of both eyes were clear and the pupils were dilated.

Liver glycogen synthase deficiency: a rarely diagnosed entity.

Unlabelled: Three children from two German families are described and the observation compared with the previously published three families comprising eight patients. The two index cases presented with morning fatigue, had ketotic hypoglycaemia when fasting which rapidly disappeared after eating, and hepatic glycogen deficiency and absent or very low hepatic glycogen synthase activity. Metabolic profiles comprising glucose, lactate, alanine, and ketones in blood were typical for hepatic glycogen synthase deficiency.

[Adult form of GM2-gangliosidosis: a man and 2 sisters with hexosaminidase-A and -B deficiency (Sandhoff disease) and literature review].

Three adult siblings had atypical progressive spinal muscular atrophy of the limb-girdle type, predominantly sensory polyneuropathy and cerebellar ataxia. Hexosaminidase A and B activity was profoundly decreased in serum, leukocytes and cultured fibroblasts. GM2-gangliosidosis, variant O (Sandhoff disease) was diagnosed.

A chondrodysplasia family produced by mutations in the diastrophic dysplasia sulfate transporter gene: genotype/phenotype correlations.

Achondrogenesis type 1B (ACG-1B), atelosteogenesis type 2 (AO-2), and diastrophic dysplasia (DTD) are recessively inherited chondrodysplasias of decreasing severity caused by mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene on chromosome 5. In these conditions, sulfate transport across the cell membrane is impaired which results in insufficient sulfation of cartilage proteoglycans and thus in an abnormally low sulfate content of cartilage. The severity of the phenotype correlates well with the predicted effect of the underlying DTDST mutations: homozygosity or compound heterozygosity for stop codons or transmembrane domain substitutions mostly result in achondrogenesis type 1B, while other structural or regulatory mutations usually result in one of the less severe phenotypes.

Gaucher disease: four families with previously undescribed mutations.

We describe four families with patients with type I Gaucher disease exhibiting previously undescribed mutations of the glucocerebrosidase gene. We found Cherokee Indian woman to have a G-->C substitution in cDNA nucleotide 354, predicting a lysine-->aspargine substitution in amino acid 79 of the processed protein. In a Greek family, we found an allele with a C-->T substitution in nucleotide 475 giving rise to an arginine-->tryptophan substitution at amino acid 120.

Spontaneous mucolipidosis in a cat: an animal model of human I-cell disease.

A 7-month-old female cat was seen for abnormal facial features and abnormality of gait. Facial dysmorphism, large paws in relation to body size, dysostosis multiplex, and poor growth were noted, and mucopolysaccharidosis was suspected. A negative urine test for sulfated glycosaminoglycans and extreme stiffness of skin indicated a mucolipidosis hitherto unknown in animals.

Early and severe sensory loss in three adult siblings with hexosaminidase A and B deficiency (Sandhoff disease).

Three siblings in their sixth and seventh decade with hexosaminidase A and B deficiency (adult form of GM2-gangliosidosis, variant O) developed early and severe sensory loss in addition to chronic motor neuron disease and cerebellar ataxia. Prominent mechanoallodynia was a manifesting symptom in two siblings. It is suggested that sensory deficits are due to a central-peripheral dying back axonopathy.

A glycine 375-to-cysteine substitution in the transmembrane domain of the fibroblast growth factor receptor-3 in a newborn with achondroplasia.

Achondroplasia, the most common form of chondrodysplasia, has been associated with mutations in the gene of the fibroblast growth factor receptor-3 (FGFR-3) on chromosome 4p. All 39 achondroplasia alleles studied so far carried point mutations which caused the same amino acid exchange, a substitution of glycine by arginine at position 380 (G380R) in the transmembrane domain of the receptor. We report on a newborn with achondroplasia who does not carry a G380R mutation but has a mutation causing substitution of a nearby glycine with a cysteine (G375C).

Galactose-1-phosphate in the pathophysiology of galactosemia.

In galactosemia, galactose-1-phosphate (gal-1-P) is not properly metabolized and accumulates in the fetus and after birth in various tissues when lactose or galactose is ingested. Well-treated galactosemics retain a low level of red cell gal-1-P which increases after breaks of diet. The ester is an indicator of the biogenesis of galactose from glucose and has been considered a pathogenic agent by inhibiting enzymes such as glucose-6-phosphatase, glucose-6-phosphate dehydrogenase, phosphoglucomutase, and glycogen phosphorylase, but the evidence remains presumptive.

Partial deficiency of galactose-1-phosphate uridyltransferase.

In screening programmes testing newborns for galactose-1-phosphate uridyltransferase and/or galactose, partial enzyme deficiency is frequently discovered. This is shown for one laboratory in Switzerland where 104 newborns were singled out from a total of 476,000. Of these, 72 had partial transferase deficiency below 9 mumol/h per g Hb and were assumed to be compound heterozygotes for "classical" galactosemia and the Duarte variant.