Gene/Protein Disease Symptom Drug Enzyme Compound
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Classical galactosaemia, deficiency of galactose-1-phosphate uridyltransferase (GALT), is characterized by acute symptoms of hepatomegaly, jaundice, sepsis, cataracts and growth retardation. Treatment with dietary galactose restriction corrects these complications immediately; however, most of these children develop long-term complications of verbal dyspraxia, mental retardation and ovarian failure. Our previous molecular study showed that the most common mutation of the GALT gene is a missense mutation of Q188R (replacement of glutamine-188 by arginine) in approximately 60-65% of the German galactosaemic population. The coding region of GALT was amplified by the polymerase chain reaction from genomic DNA of classical galactosaemic individuals, who are negative or heterozygous for Q188R, and was further characterized by direct sequencing. Three new disease-causing mutations, two missense and a stop codon mutation, were identified in three patients from two families with mild galactosaemic variants: firstly R67C, replacement of arginine-67 by cysteine and W316X, the stop codon at tryptophan-316 in one male; secondly A330V, replacement of alanine-330 by valine in two female siblings. In the first family the patient was also heterozygous for the polymorphism N314D and in the second family both girls were compound heterozygotes for Q188R and A330V. All three galactosaemic individuals have a considerable amount of the residual GALT activity in RBC and the galactose-1-phosphate (GALP) level decreased much faster on treatment than that of other galactosaemic patients with missense mutations such as Q188R. The clinical and biochemical data of these patients were much more favourable in comparison with those of two female galactosaemic individuals, one homozygous for L195P and the other compound heterozygous for Q188R and L195P. These three missense mutations (R67C, L195P and A330V) also occur in highly conserved regions. These observations suggest that the phenotypic variation in galactosaemic individuals may be due to different molecular aetiologies.
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PMID:Mutations in the galactose-1-phosphate uridyltransferase gene of two families with mild galactosaemia variants. 859 37

Approximately 0.5-1% of all newborns are born infected with cytomegalovirus (CMV), but of these only one out of ten show symptoms at birth, most often with hepatosplenomegaly, thrombocytopenia, and/or brain affection. Of the remaining nine, one may later develop sequelae with hearing loss and/or mental retardation. CMV infection may also be acquired perinatally or in the newborn period, and may cause pneumonia and/or sepsis, possibly also gastrointestinal symptoms like blood in the stool, and poor weight-gain. We have diagnosed CMV infection in ten neonates and infants, and describe these patients in terms of symptoms, diagnosis and treatment. Ganciclovir is being tested in clinical trials as a treatment for congenital CMV infection, and was given to two of our patients with apparently good results.
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PMID:[Cytomegalovirus infection in neonates. Diagnosis and therapeutic experiences]. 919 23

Mental retardation has been a controversial relative contraindication to organ transplantation. Currently, there are few data available in the literature that describe the outcome of kidney transplantation in mentally retarded patients. In a series of 1,271 kidney transplantations performed between January 1968 and March 1996, we identified eight patients (0.6%) with significant mental retardation (IQ < 70). Only cooperative patients supervised by a reliable long-term caregiver, with long life expectancy, and able to take medication under supervision, were accepted as candidates, independent of the IQ level. At a mean follow-up of 7.3 years, seven patients are alive with functioning grafts, and one lost the kidney to chronic rejection 10 years after transplantation and died of sepsis after resuming dialysis. The 1- and 5-year patient and graft survival are thus 100%. Compliance with immunosuppressive treatment and clinical follow-up was excellent in all of the recipients. The patient quality of life and health were judged by the support persons as highly improved after transplantation in comparison to dialysis. We conclude that kidney transplantation in properly selected patients with mental retardation provides excellent patient and graft survival rates and improves quality of life. In such patients, the presence of mental retardation should not be considered a contraindication to kidney transplantation.
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PMID:Kidney transplantation in recipients with mental retardation: clinical results in a single-center experience. 950 89

Classical galactosemia, characterized clinically by acute hepatic dysfunction, sepsis, cataract, and failure to thrive, is caused by deficiency of galactose-1-phosphate uridyltransferase (GALT). Galactose restriction normalizes these acute symptoms; however, long-term complications such as intellectual deficits and ovarian failure are conspicuous in the majority of patients. Here we report two Turkish siblings with classical galactosemia. The clinical course of the two children differed markedly: only the older girl suffered from severe acute symptoms during the neonatal period, and she developed greater mental retardation than her younger affected brother. The functional activity of GALT was virtually absent in each affected children. The mother and two healthy siblings exhibited approximately 50% normal GALT activity and the father approximately 25%. Molecular analysis revealed that these two galactosemic siblings were homozygous for a stop codon mutation of E340X in GALT exon 10. Moreover, two additional mutations, a neutral polymorphism L218L and N314D, which are typical for the Duarte-I variant, were found in the same GALT allele. The two healthy siblings and the parents were heterozygous for these combinations of mutations. In addition, the father's second GALT allele revealed three intron mutations at nucleotide position 1105 (G-->C), 1323 (G-->A) and 1391 (G-->A) and the N314D mutation, which correspond to the mutations of Duarte-2 variant. Our findings indicate that in classical galactosemia several distinct mutations can be present in one allele (in cis) of the GALT gene. Therefore it seems to be necessary to examine all introns and exons of the GALT gene in galactosemic patients who do not carry the Q188R mutation or another frequent mutation in the GALT gene.
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PMID:Simultaneous occurrence of various mutations and polymorphisms in cis and in trans of the galactose-1-phosphate uridyltransferase gene in a Turkish family with classical galactosemia. 976 50

Bardet-Biedl syndrome is an autosomal recessive disorder. It is characterized by cardinal anomalies including retinal dystrophy, digital malformations, mental retardation, obesity, and hypogonadism. Recently, renal anomalies also are mentioned among the cardinal signs. Although association of genital anomalies among affected boys are well known, the association of vaginal atresia and other structural genital anomalies are not mentioned among the less-common manifestations of Bardet-Biedl syndrome in girls. Two girls with Bardet-Biedl syndrome presented with hematometrocolpos in the preadolescent period and vaginal atresia was diagnosed. After surgical treatment and extended hospitalization, uncontrolled sepsis resulted in progressive renal failure and death of both patients. Vaginal atresia is often delayed or missed in the early childhood period. In girls with Bardet-Biedl syndrome, vaginal atresia or other structural genital anomalies should be evaluated more systematically during the initial diagnosis of the syndrome. In infancy, the evaluation of a child with vaginal atresia also should include the differential diagnosis of Bardet-Biedl syndrome. Vaginal atresia may either form a component of the syndrome, or girls who present with vaginal atresia in addition to other components of Bardet-Biedl syndrome might form a distinct entity.
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PMID:Vaginal atresia and Bardet-Biedl syndrome association: a component or a distinct entity? 1021 69

A cohort study at a tertiary care neonatal service was undertaken to determine the neurodevelopmental outcome of neonates who required intensive care. One hundred and nineteen nursery graduates were enrolled for follow up if they fulfilled any of the following risk factors: birth weight less than 1500 g, Apgar score less than 4 at 5 minutes, seizure(s), and required assisted ventilation for more than 24 hours. They were subjected to periodic clinical evaluation and administered the Bayley Scales of Infant Development in early childhood. Of the total infants enrolled, 101 completed the required follow up. They included 55 infants with birth weight < 1500 g, 45 with low Apgar scores, 12 with seizure(s) and 28 who received assisted ventilation. An overwhelming majority of subjects (85%) had normal neurodevelopmental outcome. The adverse outcome in the remaining 15 included mental retardation in all, subnormal motor development in 14, microcephaly in 1, hearing loss in 2 and visual impairment in 4. Among the neonatal risk factors, seizures, sepsis and hypoxic ischemic encephalopathy had a significant association with adverse outcome. Despite serious neonatal morbidity, the early neurodevelopmental outcome of nursery graduates was reasonably good. The association of neonatal sepsis with neurodevelopmental sequelae merits a prospective evaluation.
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PMID:Neurodevelopmental outcome of 'at risk' nursery graduates. 1077 50

Profound hypothermia (core temperature of less than 28 degrees C) is a life threatening state and a medical emergency associated with a high mortality rate. The prognosis depends on underlying diseases, advanced or very early age, the duration prior to treatment, the degree of hemodynamic deterioration, and especially, the methods of treatment, including active external or internal rewarming. This is a case study of an 80-year-old female patient with severe accidental hypothermia (core temperature 27 degrees C). She was found in her home lying immobile on the cold floor after a fall. The patient was in a profound coma with cardiocirculatory collapse, and the medical staff treating her was inclined to pronounce her deceased. On her arrival at the hospital, she was resuscitated, put on a respirator and actively warmed. Very severe metabolic disorders were found, including a marked metabolic acidosis composed of diabetic ketoacidosis (she had suffered from insulin treated type 2 diabetes mellitus) and lactic acidosis with a very high anion gap (42) and a hyperosmotic state (blood glucose 1202 mg/dl). There were pathognomonic electrocardiographic abnormalities, J-wave of Osborn and prolonged repolarization. Slow atrial fibrillation with a ventricular response of 30 bpm followed by a nodal rhythm of 12 bpm and reversible cardiac arrest were recorded. The pulse and blood pressure were unobtainable. Despite the successful resuscitation and hemodynamic and cognitive improvement, rhabdomyolysis (CKP 6580 u/L), renal failure and hepatic damage developed. She was extubated and treated with intravenous fluids containing dopamine, bicarbonate, insulin and antibiotics. Her medical condition gradually improved, and she was discharged clear minded, functioning very well and independent. Renal and liver tests returned eventually to normal limits. Progressive bradycardia, hypotension and death due to ventricular fibrillation or asystole commonly occur during severe hypothermia. Respiratory and metabolic, sometimes lactic, acidosis, lethargy and coma, hypercoagulopathy, hyperosmolar state, acute pancreatitis and renal and hepatic failure are frequent complications of hypothermia. Underlying predisposing causes of hypothermia are diabetic ketoacidosis, cerebrovascular disease, mental retardation, hypothyroidism, pituitary and adrenal insufficiency, malnutrition, acute alcoholism, liver damage, hypoglycemia, sepsis, hypothalamic dysfunction, sepsis and polypharmacy, and especially, the use of sedative and narcotic drugs. Our case demonstrates once again that CPR once begun should continue until the successful rewarming because "no one is dead until warm and dead".
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PMID:[Severe accidental hypothermia in an elderly woman]. 1175 73

In Oklahoma since the early 1990s, all newborns have been screened for four metabolic conditions: phenylketonuria, hypothyroidism, galactosemia and hemoglobinopathies. In 2002, 38 affected babies were diagnosed and one expects they are saved from the complications of late diagnosis such as mental retardation or death from sepsis. With advances in genetics and improved biochemical assays, 86% of states now screen for more disorders than Oklahoma, up to 37 in Mississippi. Six recent patient vignettes illustrate the mortality and morbidity of conditions that are screened for elsewhere but not in Oklahoma. In 2001, the Oklahoma Genetics Advisory Council recommended adding three disorders and the State Health Department forecasts that implementation may be complete in 2007. For now, when a patient asks, "Will my baby be screened for as many metabolic conditions as possible?", two answers represent either the public health or the private health care view. The public health answer is, "The state requires screening for four conditions." The health care system answer is, "We can work with you to get 44 conditions tested for, but it will cost money, may not be reimbursed, and has not been proven effective when done on an individual basis." This dilemma, not unique to newborn screening, might be resolved if professional and public opinion strongly supported early expansion.
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PMID:Expanding metabolic screening of newborns: can the health care industry do better than public health? 1461 2

Neisseria meningitidis is a leading cause of bacterial meningitis and sepsis in the US, Europe and in many other parts of the world, including parts of sub-Saharan Africa (known as the African 'meningitis belt'). There are > 500000 cases of meningococcal disease annually with an estimated death toll of 135000 worldwide. Approximately 10 - 15 % of survivors experience significant morbidity in the form of neurological sequelae, including hearing loss, speech disorders, loss of limbs, mental retardation and paralysis. Disease is usually caused by N. meningitidis serogroups A, B, C, Y or W-135. Prevention of meningococcal disease includes isolation, chemoprophylaxis and vaccination with available polysaccharide vaccines. However, the polysaccharide meningococcal vaccines (i.e., A and C; A, C and W-135; or A, C, Y and W-135) initially developed in the 1970s are generally poorly immunogenic in children or require repeated doses and do not produce long-lasting immunity. Conjugate vaccine technology has been very successfully used in childhood vaccines for the prevention of other bacterial meningitis pathogens, including vaccines against Haemophilus influenzae serotype b (Hib) and more recently, the seven- and nine-valent conjugate pneumococcal vaccines. Newly released meningococcal conjugate vaccines against N. meningitidis serogroup C have been highly efficacious in young children and adolescents, with minimal side effects. Conjugate vaccines targeting other important meningococcal serogroups (e.g., N. meningitidis serogroup A, responsible for the large pandemic outbreaks and the majority of disease in sub-Saharan Africa and serogroups Y and W-135) are under development and together with the serogroup C conjugates, have the potential to significantly impact worldwide sporadic and epidemic meningococcal disease. The search for an effective serogroup B meningococcal vaccine remains elusive. This manuscript reviews the conjugate meningococcal vaccines and their potential for meningococcal disease prevention.
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PMID:Meningococcal conjugate vaccines. 1510 68

Classic galactosemia is an autosomal recessive disorder that is caused by activity deficiency of the UDP-galactose uridyl transferase (GALT). The clinical spectrum of classic galactosemia differs according to the type and number of mutations in the GALT gene. Short-term clinical symptoms such as jaundice, hepatomegaly, splenomegaly and E. coli sepsis are typically associated with classic galactosemia. These symptoms are often severe but quickly ameliorate with dietary restriction of galactose. However, long-term symptoms such as mental retardation and primary ovarian failure do not resolve irrespective of dietary intervention or the period of initial dietary intervention. There seem to be an association between deficient galactosylation of cerebrosides and classic galactosemia. Galactocerebrosides and glucocerebrosides are the primary products of the enzyme UDP-galactose:cerebroside galactosyl transferase (CGT). There has been an observation of deficient galactosylation coupled with over glucosylation in the brain tissue specimens sampled from deceased classic galactosemia patients. The plausible mechanism with which the association between GALT and CGT had not been explained before. Yet, UDP-galactose serves as the product of GALT as well as a substrate for CGT. In classic galactosemia, there is a consistent deficiency in cerebroside galactosylation. We postulate that the molecular link between defective GALT enzyme, which result in classic galactosemia; and the cerebroside galactosyl transferase, which is responsible for galactosylation of cerebrosides is dependent on the cellular concentrations of UDP-galactose. We further hypothesize that a threshold concentration of UDP-galactose exist below which the integrity of cerebroside galactosylation suffers.
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PMID:The molecular relationship between deficient UDP-galactose uridyl transferase (GALT) and ceramide galactosyltransferase (CGT) enzyme function: a possible cause for poor long-term prognosis in classic galactosemia. 1612 33


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