Mary G. Ampola

Prenatal Therapy of a Patient with Vitamin-B12-Responsive Methylmalonic Acidemia

Methylmalonic acidemia due to deficient synthesis of 5-deoxyadenosylcobalamin was discovered in a mid-term fetus by culture of amniotic-fluid cells. Elevated concentrations of methylmalonic acid were also found in amniotic fluid and maternal urine. Treatment during the last nine weeks of gestation with large doses of vitamin B12 given to the mother reversed the increasing maternal excretion of methylmalonic acid, which was 23 mug per milligram of creatinine at 31 weeks gestation. Just before delivery, the mother was excreting 5 mug, two to three times normal. At birth the methylmalonic acid content of the babys urine (67 mug per milligram of creatinine) and serum (2.0 mug per milliliter) was only moderately elevated, and serum vitamin B12 concentration was very high. Acid levels rose in serum and urine in response to oral protein loading, but subsided after vitamin B12 administration. The infant is developing normally on a restricted protein diet alone at present. Prenatal therapy of methylmalonic acidemia is possible with large amount of vitamin B12 administered to the mother.

Argininemia: A Treatable Genetic Cause of Progressive Spastic Diplegia Simulating Cerebral Palsy: Case Reports and Literature Review

Argininemia, a rare autosomal recessive urea cycle disorder, is caused by a deficiency of arginase, with resulting elevated plasma arginine and ammonia levels. Reports to date have focused little on the neurology of this disorder or the efficacy of treatments. A MEDLINE search revealed 25 previously reported cases, to which we have added two brothers who presented with late onset progressive spastic diplegia. Though their degree of enzyme deficiency was comparable, the severity of their phenotypic abnormalities differed substantially. With dietary therapy, both showed improved cognitive and motor function. Late metabolic crises occurred in both, resulting in death of the less severely affected brother. Based on analysis of our clinical database, we report on the full spectrum of neurologic abnormalities seen in argininemia with particular focus on the accompanying progressive spastic diplegia and its response to treatment; progressive decline in head growth; distinctive neuroradiologic findings; and life-threatening later complications. Current and potential future therapies and long-term outcome are summarized. (J Child Neurol 1997;12:301-309).

New England Maternal PKU Project: Prospective study of untreated and treated pregnancies and their outcomes*

Four women with classic phenylketonuria (blood phenylalanine greater than 1200 mumol/L) were given a phenylalanine-restricted diet; three also received L-tyrosine supplements. Biochemical measures of nutrition were normal except for iron deficiency anemia, and in one woman folate deficiency. One pregnancy in which treatment began before conception and another treated from 8 weeks gestation, both with blood phenylalanine levels maintained at 120 to 730 mumol/L, resulted in normal newborn infants whose postnatal growth and development have also been normal. A third pregnancy, treated from 6 gestational weeks, was marked by poor dietary compliance until the middle of the second trimester; fetal microcephaly was identified by ultrasonography at 28 weeks but not at 21 weeks. The child has microcephaly and motor delay. The fourth pregnancy, not treated until the third trimester, produced a child with microcephaly, mental retardation, hyperactivity, and neurologic deficits. It is likely that fetal damage from maternal phenylketonuria can be largely and perhaps entirely prevented by dietary therapy, but therapy must begin before conception for the best chance of a normal infant.

Infantile hypermethioninemia and hyperhomocysteinemia due to high methionine intake: a diagnostic trap

Studies were carried out to identify the cause of combined severe hypermethioninemia and moderate hyperhomocysteinemia in a cluster of 10 infants ascertained between 1999 and early 2001. Although several were thought initially to have cystathionine beta-synthase (CBS) deficiency and treated accordingly, CBS deficiency and other known genetic causes of hypermethioninemia were ruled out by assay of CBS activity in fibroblasts of four patients and by assays of plasma cystathionine and S-adenosylmethionine. Retrospective data on dietary methionine intakes and plasma concentrations of methionine and related metabolites established that the hypermethioninemia in nine of the 10 babies was related to ingestion of an infant protein hydrolysate formula, the methionine content of which had been increased from May 1998 to February 2001. The formula in question has now been reformulated and is no longer available. The 10th infant manifested similar metabolic abnormalities while receiving TPN containing excessive methionine. Brain MRI abnormalities indicative of cerebral edema, most marked in the cerebral cortex and posterior brainstem, occurred in two patients near times of extreme hypermethioninemia. Metabolic and MRI abnormalities resolved when the methionine intake decreased. A third infant had a normal MRI 1 day after the formula was changed. The possible relationship between extreme hypermethioninemia and cerebral edema is discussed and a working hypothesis offered to explain the relative sensitivity of the inferior colliculi, based upon the facts that this is the region most active in glucose utilization and that Na(+),K(+)-ATPase is inhibited by methionine and related metabolites.

Diagnosis of Unsuspected Fetal Metabolic Storage Disease by Routine Placental Examination

GM1 gangliosidosis (type 1) is a rare hereditary, autosomal recessive, lysosomal storage disease characterized by a marked deficiency of active acid beta-galactosidase resulting in accumulation of gangliosides and mucopolysaccharides in tissues. Disease status of newborns from affected kindreds may be diagnosed by placental examination. Typical findings include a characteristic vacuolar distension of the cytoplasm of syncytiotrophoblast and stromal Hofbauer cells. We report a case of unsuspected fetal storage disorder initially diagnosed by routine placental examination of a normal-appearing infant born to a previously unaffected family. Progressive, third-trimester oligohydramnios and fetal growth retardation had been documented by ultrasonography. Placental findings included vacuolization of syncytiotrophoblast, intermediate trophoblast, and stromal Hofbauer cells. Subsequent enzyme analysis confirmed the placental findings of storage disorder and diagnosed GM1 gangliosidosis.

Newborn screening compared to clinical identification of biochemical genetic disorders

A group of 28 patients with inherited metabolic disease (homocystinuria galactosaemia, maple syrup urine disease and biotinidase deficiency) diagnosed by screening were compared with a group of 17 similar patients identified clinically. The rate of hospitalization was similar for the two groups. The patients diagnosed clinically showed a higher incidence of mental retardation and their parents experienced greater stress and found greater difficulty in meeting their childs needs.

Combined interactive computer measurement and automatic classification of human chromosomes.

A computer system to both measure and classify human chromosomes with good accuracy compared to manual methods is described. Using a 35-mm photomicrographic negative, the system, while measuring the chromosomes automatically, requires a human operator’s interaction for about 15% of the chromosomes. Results for an initial 45 spreads are given. Using the interactively measured arm lengths and arm areas, the system classified over 99% of the chromosomes correctly into 10 classes without any assistance; two chromosomes, or 0.1% of the initial sample, were misclassified (from group D to E). For the remaining 1%, interaction after classification was requested by the computer, and, with the information available to the operator, a correct classification can be made in these cases by him. The system uses a computer-controlled flying spot scanner connected to a medium-size general purpose computer, an IBM 360 Series, Model 30, and takes 25 min per spread. An annual capacity of 7500 analyzed spreads will be available in 1971 after installation of an RCA Spectra 70/46, operating under a multi-programmed system, in October 1970. Applications for the system may depend on cytogeneticists exploiting its advantages and avoiding the drawbacks described.

New England Consortium: a model for medical evaluation of expanded newborn screening with tandem mass spectrometry.

Newborn screening by tandem mass spectrometry (MS-MS), enabling presymptomatic identi¢cation of more than 20 inborn errors of metabolism, is used in several screening programmes throughout the world (Levy and Albers 2000).Most disorders identi¢ed by this technology are still incompletely understood. Consequently, there is a need to gather information about the bene¢ts of presymptomatic identi¢cation of these disorders and to develop a comprehensive system of management for this new group of identi¢ed newborns. In New England, it was felt that these objectives could best be realized through a consortium of those involved in screening and those who provide metabolic management. A consortium would also offer the unique opportunity to compare the outcome between infants detected presymptomatically and those diagnosed clinically, an opportunity presented because, in New England, only the state of Massachusetts has yet fully integrated MS-MS into newborn screening. The state of Maine also allows this technology for expanded screening, but only for medium-chain acyl-CoA dehydrogenase de¢ciency (MCADD). The main goal of the New England Consortium is the integration of newborn screening, metabolic evaluation, primary care and research into a comprehensive and e¤cient system for management of metabolic patients (Figure 1). The primary care physician, considered the medical home, occupies an active role in the general care of the child in this proposed system. Following newborn screening detection and con¢rmation of a metabolic disorder, the Consortium provides this physician with the most recent information about the disorder and recommendations for emergency care as well as general paediatric follow-up. The management of the child is then coordinated among the metabolic centre, the primary care physician and the family. The primary care physician is invited to join the Consortium, which also includes representatives from other metabolic centres, the New England Newborn Screening Program and parent groups. Exchange of information is facilitated by awebsite that contains information on the metabolic diseases identi¢able by MS-MS, on social support programmes and on advances in research ( ). Consortium members meet anually to exchange experiences and report on recent developments. J. Inherit. Metab. Dis. 24 (2001) 303^304 # SSIEM and Kluwer Academic Publishers. Printed in the Netherlands.

Congenital Expression of Prolidase Defect in Prolidase Deficiency

Summary: Newborn blood from three siblings with prolidase deficiency contained no detectable prolidase activity. Umbilical cord blood contained no prolidase activity in one sibling and only 6.8% of control activity in another sibling. In prolidase deficiency the enzyme defect is expressed at birth, well before the appearance of skin ulcers, and is demonstrable in filter paper specimens of blood obtained for routine screening.

Intermittent dystonia in Hartnup disease

A 6-month-old girl developed intermittent dystonic posture of the legs and eczematous dermatitis without ataxia. Qualitative and quantitative urine amino acid testing confirmed the diagnosis of Hartnup disease. Cranial computed tomography, electroencephalogram, electromyogram/nerve conduction study, posterior tibial somatosensory evoked potentials, 24-hour electroencephalographic telemetry, and metrizamide myelogram were normal. Spinal fluid hydroxy-indoleacetic acid concentration was less than or equal to 2 S.D. of normal; oral tryptophan loading (70 mg/kg) resulted in a two-fold rise in cerebrospinal fluid 5-hydroxy-indoleacetic acid concentration. Tryptophan administered alone or with nicotinic acid failed to improve the dystonia; however, trihexyphenidyl (1-2 mg/kg/day) dramatically improved it. Hartnup disease should be considered in children with unexplained dystonia.