Clinical and metabolic correction of pompe disease by enzyme therapy in acid maltase-deficient quail.

Pompe disease is a fatal genetic muscle disorder caused by a deficiency of acid alpha-glucosidase (GAA), a glycogen degrading lysosomal enzyme. GAA-deficient (AMD) Japanese quails exhibit progressive myopathy and cannot lift their wings, fly, or right themselves from the supine position (flip test). Six 4-wk-old acid maltase-deficient quails, with the clinical symptoms listed, were intravenously injected with 14 or 4.2 mg/kg of precursor form of recombinant human GAA or buffer alone every 2-3 d for 18 d (seven injections). On day 18, both high dose-treated birds (14 mg/kg) scored positive flip tests and flapped their wings, and one bird flew up more than 100 cm. GAA activity increased in most of the tissues examined. In heart and liver, glycogen levels dropped to normal and histopathology was normal. In pectoralis muscle, morphology was essentially normal, except for increased glycogen granules. In sharp contrast, sham-treated quail muscle had markedly increased glycogen granules, multi-vesicular autophagosomes, and inter- and intrafascicular fatty infiltrations. Low dose-treated birds (4.2 mg/kg) improved less biochemically and histopathologically than high dose birds, indicating a dose-dependent response. Additional experiment with intermediate doses and extended treatment (four birds, 5.7-9 mg/kg for 45 d) halted the progression of the disease. Our data is the first to show that an exogenous protein can target to muscle and produce muscle improvement. These data also suggest enzyme replacement with recombinant human GAA is a promising therapy for human Pompe disease.

Outcome after three years of laronidase enzyme replacement therapy in a patient with Hurler syndrome.

Enzyme replacement therapy (ERT) with laronidase, recombinant alpha-L-iduronidase, for mucopolysaccharidosis type I (MPS I) has been clinically available since April 2003. Pre-approval studies were performed on patients with the more attenuated forms of MPS I, Hurler-Scheie and Scheie syndromes. The clinical efficacy of laronidase on the severe form of MPS I, Hurler syndrome, is not well known. We present a patient with Hurler syndrome who has been treated with laronidase for 3 years. Clinically, the patient demonstrated improvement in urinary glycosaminoglycan (GAG) levels and hepatomegaly, but continued to experience decline in respiratory status, musculoskeletal and spinal involvement, and developmental skills. Overall, the benefit of ERT with laronidase in advanced Hurler syndrome appeared to be minimal in this patient.

Acute hydrocephalus in nonketotic hyperglycinemia.

We present four patients with typical neonatal onset non-ketotic hyperglycinemia (NKH) who developed hydrocephalus requiring shunting in early infancy. Brain imaging revealed acute hydrocephalus, a megacisterna magna or posterior fossa cyst, pronounced atrophy of the white matter, and an extremely thin corpus callosum in all. The three older patients had profound developmental disabilities. This suggests that the development of hydrocephalus in NKH is an additional poor prognostic sign.

Cerebral defects and nephrogenic diabetes insipidus with the ARC syndrome: additional findings or a new syndrome (ARCC-NDI)?

We report on 4 children from 2 unrelated families who appear to have the lethal ARC syndrome (arthrogryposis, renal tubular dysfunction, and cholestasis) together with the additional findings of nephrogenic diabetes insipidus and cerebral anomalies, including deafness. With increased survival time in our patients, paucity of the intrahepatic bile ductules and cholestasis progressed to cirrhosis, growth was severely impaired, and severe mental retardation became apparent. No evidence was found for peroxisomal, chromosomal, or mitochondrial disorders. We propose to amend the ARC mnemonic to ARCC-NDI (A-Arthrogryposis, R-renal Fanconi, C-cerebral, C-cholestasis, NDI-nephrogenic diabetes insipidus) to name the major manifestations of this syndrome, several of which have not been appreciated.

Molybdopterin synthase mutations in a mild case of molybdenum cofactor deficiency.

Molybdenum cofactor deficiency is a rare inborn error of metabolism with generally severe symptoms, most often including neonatal seizures and severe developmental delay. We describe a patient with an unusually mild form of the disease. Two mutations in MOCS2A (molybdenum cofactor synthesis enzyme 2A) were identified: a single base change, 16C > T, that predicts a Q6X substitution on one allele and a 19G > T transversion that predicts a valine to phenylalanine substitution, V7F, on the second. It is postulated that the milder clinical symptoms result from a low level of residual molybdopterin synthase activity derived from the 19G > T allele.

Unbalanced translocation 46,XY,-15,+der(22)t(15;22)(q13;q11)pat: case report and review of the literature.

We present a boy with a rare unbalanced translocation 46,XY,-15,+der(22),t(15;22)(q13;q11) pat. Previous reports of similar chromosome findings mention only the Prader-Willi phenotype. At birth, his manifestations included severe hypotonia and lethargy, (typical of deletion of 15pter----q13); hypertelorism, down-slanting small palpebral fissures, preauricular tags, long philtrum (typical of duplication of 22pter----q11); severe laryngotracheomalacia, and proximal implantation of the thumb. In a review of the literature on chromosome abnormalities involving duplication of 22q11 the associated clinical phenotype consists of mild mental retardation, microcephaly, hypotonia, hypertelorism, down-slanting palpebral fissures, a long philtrum, cleft or highly arched palate, and ear abnormalities. Preauricular pits or tags are common. Cardiovascular defects, renal and genital problems and dislocated hips are frequently present. Anal atresia and colobomata are mainly seen in cat-eye syndrome, the phenotype associated with idic 22q11. Our findings indicate that patients with unbalanced t(15;22) can have manifestations of the dup 22q11, in addition to the previously reported Prader-Willi phenotype, even if the duplicated segment is small.

Fryns syndrome survivors and neurologic outcome.

Fryns syndrome is an autosomal recessive multiple congenital anomaly syndrome characterized by diaphragmatic hernia, unusual facies, and distal limb hypoplasia. It was first reported as a lethal condition. We report on a three-year-old survivor with Fryns syndrome, and provide a review on the outcome of other survivors. Patients who survive the neonatal period represent 14% of reported cases. Characteristics of survivors include less frequent diaphragmatic hernia and milder lung hypoplasia, absence of complex cardiac malformation, and neurologic impairment. Multiple central nervous system abnormalities have been reported in Fryns syndrome, including agenesis of the corpus callosum, Dandy-Walker abnormality, cerebellar heterotopias, cerebellar hypoplasia, enlarged ventricles, and hypoplasia of the olfactory bulbs. Our patient exhibited profound mental retardation. He had malformations of gyration and sulcation, particularly around the central sulcus, and hypoplastic optic tracts beyond the optic chiasm. Understanding of long-term outcome of survivors is important for counseling of families with Fryns syndrome. Careful brain examination is advised; however, a normal radiological brain examination does not preclude developmental delay. The spectrum of individual outcome and of associated anomalies indicates that individual evaluation, including imaging for structural brain malformation, is strongly advised.

Hemangioma, supraumbilical midline raphé, and coarctation of the aorta with a right aortic arch: single causal entity?

Most congenital cutaneous hemangiomas are a sporadic occurrence. Hemangiomas have been found in association with coarctation of the aorta and a right aortic arch. A separate association has been noted of midline ventral defects with hemangiomas. We report on a patient with multiple hemangiomas, coarctation of the aorta and a right aortic arch, a superaumbilical midabdominal raphé and sternal cleft. Our patient represents an overlap between these two conditions. Review of the literature identified four additional patients with a similar combination of anomalies. The clinical overlap between these 5 patients suggests that they are variants of the same conditions and represent a spectrum of defects that includes hemangiomas, midline ventral defects, aortic arch abnormalities and brain malformation.

Treatment of pyruvate carboxylase deficiency with high doses of citrate and aspartate.

A patient with severe pyruvate carboxylase deficiency presented at age 11 weeks with metabolic decompensation after routine immunization. She was comatose, had severe lactic acidemia (22 mM) and ketosis, low aspartate and glutamate, elevated citrulline and proline, and mild hyperammonemia. Head magnetic resonance imaging showed subdural hematomas and mild generalized brain atrophy. Biotin-unresponsive pyruvate carboxylase deficiency was diagnosed. To provide oxaloacetate, she was treated with high-dose citrate (7.5 mol/kg(-1)/day(-1)), aspartate (10 mmol/kg(-1)/day(-1)), and continuous drip feeding. Lactate and ketones diminished dramatically, and plasma amino acids normalized, except for arginine, which required supplementation. In the cerebrospinal fluid (CSF), glutamine remained low and lysine elevated, showing the treatment had not normalized brain chemistry. Metabolic decompensations, triggered by infections or fasting, diminished after the first year. They were characterized by severe lactic and ketoacidosis, hypernatremia, and a tendency to hypoglycemia. At age 3(1/2) years she has profound mental retardation, spasticity, and grand mal and myoclonic seizures only partially controlled by anticonvulsants. The new treatment regimen has helped maintain metabolic control, but the neurological outcome is still poor.

Niemann-Pick disease type B: an unusual clinical presentation with multiple vertebral fractures.

We report here a unique case of a 55-year-old woman presenting with a clinical picture of Parkinson disease, severe back pain, splenomegaly, and pronounced dyspnea. Radiographic examination of the spine showed multiple vertebral fractures. Niemann-Pick disease type B was diagnosed by findings of lipid-loaded histiocytes and a strongly reduced sphingomyelinase enzyme activity. She was homozygous for the deletion of codon 608 (delR608), which encodes an arginine residue in the Acid Sphingomyelinase gene. To investigate the cause of the unusual vertebral fractures, we screened for polymorphisms previously described as possibly associated with increased risk for osteoporosis and fractures. Our patient was heterozygous for the polymorphisms of the vitamin D receptor gene, the estrogen receptor gene, and the collagen 1A1gene. Increased physical activity after Parkinson treatment, a genetic predisposition, together with worsening disease due to interfering medications could explain the dramatic presentation of this patient. She was treated with cholesterol lowering drugs such as statins to decrease sphingomyelin synthesis, avoidance of drugs that inhibit sphingomyelinase, and bisphosphonates. No new fractures have occurred, but the interstitial lung disease has progressed.

Mitochondrial myopathy with anemia, cardiomyopathy, and lactic acidosis: a distinct late onset mitochondrial disorder.

A 40-year-old woman presented with profound muscle weakness resulting in failure to wean from a ventilator and persistent lactic acidosis after having recovered from a pneumonia complicated by adult respiratory distress syndrome, myocardial infarction, renal failure and shock. She had a 28 year history of chronic anemia and exercise intolerance. Anemia and thrombocytopenia persisted after admission. Nonobstructive hypertrophic cardiomyopathy was present. A stroke-like episode occurred. A mitochondrial myopathy with deficiencies in complexes IV and II was demonstrated, but no DNA defect has yet been found. This patient represents a distinct clinical presentation of a mitochondrial disorder characterized by late onset mitochondrial myopathy, chronic anemia, cardiomyopathy, and lactic acidosis.

Benzoate therapy and carnitine deficiency in non-ketotic hyperglycinemia.

Five patients presenting with non-ketotic hyperglycinemia in the neonatal period were treated with sodium benzoate to normalize plasma glycine levels. This therapy resulted in seizure reduction and a marked increase in wakefulness. Plasma carnitine deficiency was noted in three of four patients tested, and benzoylcarnitine was identified in plasma, urine, and CSF. Treatment with L-carnitine normalized plasma free carnitine. L-carnitine showed a tendency to increase the glycine conjugation of benzoate. An episode of coma and increased seizures in one patient was associated with a toxic level of benzoate, probably due to insufficient mobilization of glycine for conjugation. High dose benzoate therapy improved the quality of life of surviving patients. Close monitoring of glycine, benzoate and carnitine levels is advised.

Pelvi-perineal rehabilitation for dysfunctioning erections. A clinical and anatomo-physiologic study.

We have studied penile structure in 24 cadaver specimens and 155 patients have been treated for organic impotence by physiotherapy. Special attention has been focused on the closure mechanism of the corpora cavernosa during erection. We have found that the leakage factor of the corpora cavernosa is, among other things, influenced by the ischiocavernous muscles. Based on the above, we propose a model for the anatomic and physiologic basis of interference of the ischiocavernous muscles in venous occlusion during penile erection. Moreover we suggest that patients with erectile dysfunction should undergo pelvi-perineal rehabilitation in order to strengthen and control ischiocavernous muscles.

Non-endemic Burkitt's lymphoma in a patient with Bloom's syndrome.

Bloom's syndrome is an autosomal recessive disorder characterized by intrauterine growth retardation, typical physical signs, immunodeficiency and an increased risk of developing neoplasms at a young age, compared to the general population. Factors possibly involved in the pathogenesis of non-endemic Burkitt's lymphoma in a five year old girl with Bloom's syndrome are discussed. These include immunodeficiency, upregulated c-myc expression and an Epstein-Barr viral infection.

[Treatment of Pompe's disease with recombinant enzymes]. / Behandeling van de ziekte van Pompe met recombinant enzym.

Pompe disease is caused by the congenital deficiency of the lysosomal enzyme acid alpha-glucosidase. The accumulation of lysosomal glycogen results in a fatal myopathy and cardiomyopathy. We developed an enzyme replacement therapy based on recombinant human acid alpha-glucosidase enzyme targeted to the organs of interest by the presence of mannose-6-phosphate on this precursor enzyme and a manose-6-phosphate receptor present in muscle and heart. Using molecular techniques and following extensive selection, Chinese hamster ovary cells were developed that produced very large quantities of precursor human acid alpha-glucosidase in the culture medium. An improved method of purification of this precursor enzyme from tissue culture medium was developed. This purified precursor enzyme was taken up efficiently by patient's fibroblasts, and corrected with a single dose the lysosomal glycogen accumulation for one week. Finally, intravenous administration of the recombinant enzyme corrected the pathology and symptoms of an animal model of this disorder, the acid alpha-glucosidase deficient Japanese quail.

Ophthalmological findings in a patient with mucolipidosis III (pseudo-hurler polydystrophy). A case report.

Mucolipidosis III (Pseudo-Hurler Polydystrophy) is a rare autosomal recessively inherited Hurler-like disease. The ophthalmological findings in these patients include a triad of mild retinopathy, corneal clouding and hyperopic astigmatism. We present a patient with these ophthalmological characteristics.

Transcriptional profiling of the lectin ArathEULS3 from Arabidopsis thaliana toward abiotic stresses.

The family of EUL-related lectins groups all proteins with an Euonymus lectin (EUL) domain, a protein motif which is highly conserved throughout the plant kingdom and occurs as part of many chimeric proteins with different domain architectures. The S3 type EUL lectin from Arabidopsis thaliana (ArathEULS3) has become the model protein within this EUL family. Based on sequence homology to an ABA/NaCl inducible gene from rice and some publicly available high-throughput micro-array data, it was hypothesized that ArathEULS3 is transcriptionally regulated by osmotic stress responses. Here we present a detailed expression analysis of the ArathEULS3 lectin gene. Under normal growth conditions, ArathEULS3 is stably expressed throughout plant development. After ABA, NaCl and methyl jasmonate (MeJA) treatments transcription is upregulated. Furthermore, in silico promoter and co-expression analyses suggested the A. thaliana Homeobox 7 (ATHB-7) as a candidate transcription factor that may regulate ArathEULS3 expression. Taken together, our data confirm that the ArathEULS3 lectin gene indeed shows a stress-inducible expression pattern. We speculate on a role for ArathEULS3 in the plant stress response.

MRI of the brain and cervical spinal cord in rhizomelic chondrodysplasia punctata.

BACKGROUND: The classic rhizomelic chondrodysplasia punctata (RCDP) phenotype involves a typical facial appearance, cataracts, skeletal dysplasia causing disproportionate somatic growth failure, microcephaly, and severe psychomotor defects. Biochemical abnormalities include impaired plasmalogen biosynthesis in all forms of RCDP and accumulation of phytanic acid in RCDP type 1. A subset of patients has a milder clinical and biochemical phenotype, with less severe neurologic impairment and an incomplete deficiency in plasmalogens. The impact of plasmalogen deficiency on neurologic function is severe, causing spasticity and mental defects, but its pathomechanism is still unknown. The authors specifically focused on myelination because myelin is rich in ethanolamine plasmalogens. OBJECTIVE: To define the neuroimaging characteristics of the genetic peroxisomal disorder RCDP. METHODS: Twenty-one MR images of the brain and cervical spine of 11 patients were evaluated and correlated with neurologic and biochemical profiles. RESULTS: No abnormalities on MRI were seen in the patients with a mild phenotype of RCDP, whereas delayed myelination, ventricular enlargement and increased subarachnoidal spaces, supratentorial myelin abnormalities, and cerebellar atrophy were observed in patients with the severe phenotype of both RCDP type 1 and 3. The severity of both the MRI abnormalities and the clinical phenotype is correlated with the plasmalogen level. CONCLUSIONS: The severe phenotype of rhizomelic chondrodysplasia punctata (RCDP) is accompanied by a specific pattern of both developmental and regressive MRI abnormalities. Plasmalogen levels seem to play an important role in the pathophysiology of CNS abnormalities in RCDP. Increased phytanic acid appears not to be the cause of cerebellar atrophy.

Expanded motor and psychiatric phenotype in autosomal dominant Segawa syndrome due to GTP cyclohydrolase deficiency.

BACKGROUND: Segawa syndrome due to GTP cyclohydrolase deficiency is an autosomal dominant disorder with variable expression, that is clinically characterised by l-dopa responsive, diurnally fluctuating dystonia and parkinsonian symptoms. OBJECTIVE: To delineate the neurological and psychiatric phenotype in all affected individuals of three extended families. METHODS: GTP cyclohydrolase deficiency was documented by biochemical analyses, enzymatic measurements in fibroblasts, and molecular investigations. All affected individuals were examined neurologically, and psychiatric data were systematically reviewed. RESULTS: Eighteen affected patients from three families with proven GTP cyclohydrolase deficiency were identified. Eight patients presenting at less than 20 years of age had typical motor symptoms of dystonia with diurnal variation. Five family members had late-presenting mild dopa-responsive symptoms of rigidity, frequent falls, and tendonitis. Among mutation carriers older than 20 years of age, major depressive disorder, often recurrent, and obsessive-compulsive disorder were strikingly more frequent than observed in the general population. Patients responded well to medication increasing serotonergic neurotransmission and to l-dopa substitution. Sleep disorders including difficulty in sleep onset and maintenance, excessive sleepiness, and frequent disturbing nightmares were present in 55% of patients. CONCLUSION: Physicians should be aware of this expanded phenotype in affected members of families with GTP cyclohydrolase deficiency.

Benzoate treatment and the glycine index in nonketotic hyperglycinaemia.

High-dose benzoate treatment aimed at reducing plasma glycine levels to normal reduces seizures and increases wakefulness in patients with nonketotic hyperglycinaemia (NKH). Since benzoate metabolism is dependent on the available glycine pool, and since the glycine pool is variably affected by the deficiency in the glycine cleavage enzyme system, we examined the importance of interpatient variability in benzoate requirement. To correct for the dietary glycine contribution, the glycine index was introduced as the molar requirement of benzoate dose necessary to normalize plasma glycine levels and subtracting from that the dietary glycine intake, both corrected for weight. The glycine index varied between 3.62 and 4.87 mmol/kg per day in five patients with a poor neurodevelopmental outcome and between 0.92 and 1.90 mmol/kg per day in four patients with a better neurodevelopmental outcome, and was 2.54 mmol/kg per day in a single patient with an intermediate outcome. The glycine index was stable over time within each patient. Exceeding the balance by either increasing food glycine intake or decreasing the benzoate dose resulted in increased glycine levels. Exceeding the glycine tolerance by increasing benzoate resulted in elevated and toxic levels of benzoate. The glycine index is a stable, individually specific parameter in patients with NKH. It has clinical consequences for the dose of benzoate required and the role of dietary management. Through its correlation with neurodevelopmental outcome, the glycine index points to potential genetic factors that could contribute to the psychomotor retardation in NKH.