Bone marrow transplantation for infantile ceramidase deficiency (Farber disease).

Infantile ceramidase deficiency (Farber disease) is an uncommon, progressive lysosomal storage disease characterized by multiple ceramide-containing nodules (lipogranulomata) in the subcutaneous tissue and upper aerodigestive tract, painful periarticular swelling, psychomotor retardation, and varying degrees of ocular, pulmonary or hepatic involvement. Management of Farber disease has been limited to symptomatic supportive care, and few affected infants survive beyond 5 years of age. We performed an allogeneic bone marrow transplant (BMT) from an HLA-identical heterozygous sister in a 9.5-month-old female with minimally symptomatic Farber disease who received a pre-transplant regimen of busulfan and cyclophosphamide. Ceramidase activity in peripheral blood leukocytes increased from 6% before transplant to 44% (donor heterozygote level) by 6 weeks after BMT. By 2 months after transplant, the patient's subcutaneous lipogranulomata, pain on joint motion, and hoarseness had resolved. Despite modest gains in cognitive and language development, hypotonia and delayed motor skills persisted. Gradual loss of circulating donor cells with autologous hematopoietic recovery occurred; VNTR analyses showed 50% donor DNA in peripheral blood cells at 8.5 months after BMT and only 1% at 21 months after transplant. Interestingly, leukocyte ceramidase activity consistently remained in the heterozygous range despite attrition of donor cells in peripheral blood. This novel observation indicates ongoing hydrolase production by non-circulating donor cells, possibly in the mononuclear phagocytic system, and uptake by recipient leukocytes. Although lipogranulomata and hoarseness did not recur, the patient's neurological and neurocognitive status progressively declined. She died 28 months after BMT (age 37.5 months) with pulmonary insufficiency caused by recurrent aspiration pneumonias. Allogeneic BMT improves the peripheral manifestations of infantile ceramidase deficiency, but may not prevent the progressive neurological deterioration, even when carried out in minimally symptomatic patients.

Acute hypoxia activates human 8-12 Hz physiological tremor.

Hypoxia causes arousal. Therefore, we hypothesized that hypoxia activates the human somatomotor system and should augment tremor. We determined the effects of hypoxia, PET(O2) = 45+/-2.2 mm Hg, hypocapnia, and the hypocapnic-hypoxic interaction on finger tremor during elastic loading. A total of 12 healthy male volunteers were studied during five conditions: eupnea, hypocapnic hypoxia, eucapnic hypoxia, hypocapnic normoxia, and eucapnic normoxia. Acceleration power spectra were computed to quantify 8-12 Hz tremor. Hypoxia significantly augmented 8-12 Hz physiological tremor (P=0.002). Furthermore, six subjects (50%) exhibited significantly more tremor during hypocapnic hypoxia (hH) than during eucapnic hypoxia (eH). We conclude that acute hypoxia augments 8-12 Hz physiological tremor, and hypocapnia further augments this tremor in some subjects. As such, hypoxic tremor is activated physiological tremor, and entrainment of spinal alpha-motoneuron activity may be the final common pathway.

Cervical neurofibromas in children with NF-1.

BACKGROUND: Children with neurofibromatosis type 1 (NF1) are at increased risk of developing plexiform neurofibroma throughout the body, including the cervical soft tissues. However, the incidence of cervical soft tissue tumors and the value of screening MR for children with NF1 are not known. PURPOSE: The purposes of this study were to determine the incidence and clinical significance of cervical tumors seen on MR imaging in children with NF1. MATERIALS AND METHODS: A retrospective review of the brain and orbit MR with cervical images obtained on 95 children who meet the NIH consensus criteria for NF1 and who are followed at our neurofibromatosis clinic was carried out. RESULTS: Cervical tumors were found on MR imaging in 21 of 95 (22%) children. Of 21 children with cervical tumors, 14 children were determined to be surgical candidates. In nine children, MR imaging altered the clinical management by demonstrating tumors for which surgery was indicated, but the tumors were not suspected prior to MR imaging. CONCLUSION: Cervical tumors are commonly seen in children with NF1. MR imaging may demonstrate a significant number of tumors that require surgery, but were not suspected prior to MR imaging.

Potential role for imidazole in the rhythmic respiratory activity of the in vitro neonatal rat brainstem.

We used the imidazole-binding agent, diethylpyrocarbonate (DEPC), to test the hypothesis that rhythmic respiratory activity of the in vitro neonatal rat brainstem-spinal cord preparation was functionally dependent on imidazole. Neural activity was recorded from spinal nerves (C1-C4) during superfusion with 95%O2/5%CO2 buffer at pH 7.3 and T = 26 degrees C. Superfusate containing DEPC (40 mM) caused cessation of rhythmic activity within minutes. In eight of 33 preparations, microinjection of DEPC (32 nmol) onto the ventral medullary surface (VMS) reduced burst amplitude by at least 50% within 10 min, and in 12 of 33 preparations, microinjection of DEPC produced neural apnea. Therefore, we conclude that proteins containing imidazole near the VMS are critically important for the maintenance of rhythmic respiratory activity in vitro. Furthermore, alphastat regulation of respiration may be an essential trait of this preparation.

Mutation in fibrillin-1 and the Marfanoid-craniosynostosis (Shprintzen-Goldberg) syndrome.

Recent reports have described a distinct and recurrent pattern of systemic malformation that associates craniosynostosis and neurodevelopmental abnormalities with many clinical features of the Marfan syndrome (MFS), an autosomal dominant disorder of the extracellular microfibril caused by defects in the gene encoding fibrillin-1, FBN1 (ref. 8). Additional common findings include other craniofacial anomalies, hypotonia, obstructive apnea, foot deformity, and congenital weakness of the abdominal wall. So far, only 11 cases have been reported precluding the assignment of definitive diagnostic criteria. While it remains unclear whether these cases represent a discrete clinical entity with a single aetiology, they have been pragmatically grouped under the rubric Marfanoid-craniosynostosis or Shprintzen-Goldberg syndrome (SGS). Because of the significant clinical overlap between MFS and SGS, we proposed that they may be caused by allelic mutations. We now report two SGS patients who harbour mutations in FBN1. While it remains unclear whether these mutations are sufficient for the clinical expression of the entire SGS phenotype, these data suggest a role for fibrillin-1 in early craniofacial and central nervous system development. Our recent observation that FBN1 transcript is expressed as early as the 8-cell stage of human embryogenesis is consistent with this hypothesis.

Plasma amino acid concentrations and amino acid ratios in normal adults and adults heterozygous for phenylketonuria ingesting a hamburger and milk shake meal.

Plasma amino acid concentrations were measured and selected amino acid ratios were calculated in 12 normal adults and 12 adults heterozygous for phenylketonuria (PKU) ingesting a hamburger and milk shake meal providing 1 g protein/kg body wt. Plasma concentrations of all amino acids increased significantly over baseline after meal ingestion in both groups, reaching the highest mean values 3-5 h after meal ingestion. Plasma phenylalanine concentrations were significantly higher in heterozygous than in normal subjects both before and at all times after meal ingestion. The absolute increase in plasma phenylalanine concentration over baseline and the area under the plasma phenylalanine concentration-time curve were approximately twice as large in heterozygous as in normal subjects. However, the molar ratio of the plasma phenylalanine concentration to the sum of the plasma concentrations of the other large neutral amino acids did not increase significantly over baseline, but rather decreased.

Repeated ingestion of aspartame-sweetened beverages: further observations in individuals heterozygous for phenylketonuria.

Six adults heterozygous for phenylketonuria (PKU) ingested eight successive servings of unsweetened and aspartame (APM)-sweetened beverage at 1-hour intervals in a randomized, balanced, crossover design. In one part, the eight beverage servings were not sweetened. In the other, each of the eight beverage servings provided 600 mg of APM, a dose equivalent to the amount provided by 36 oz of an APM-sweetened diet beverage. Plasma aspartate concentration was not significantly increased after ingestion of unsweetened or APM-sweetened beverage. Similarly, ingestion of the unsweetened beverage had no significant effect on plasma phenylalanine concentration. However, ingestion of APM-sweetened beverage significantly increased plasma phenylalanine concentrations 2.35 to 4.03 mumol/dL above baseline 30 minutes after ingestion. Plasma phenylalanine values reached a steady-state after administration of five servings of APM-sweetened beverage and were slightly, but significantly higher than usual postprandial values for adults heterozygous for PKU. Similarly, the ratio of the plasma phenylalanine concentration to the sum of the concentration of the large neutral amino acids was significantly higher than usual postprandial values. Blood methanol and formate concentrations remained within normal limits. These data indicate that a fasting adult heterozygous for PKU could consume the equivalent of 24 12-oz servings of APM-sweetened beverage over an 8-hour period and only increase plasma phenylalanine concentration to a modest degree.

Aspartame ingestion with and without carbohydrate in phenylketonuric and normal subjects: effect on plasma concentrations of amino acids, glucose, and insulin.

Seven subjects homozygous for phenylketonuria (PKU) and seven normal subjects were administered four beverage regimens after an overnight fast: unsweetened beverage, beverage providing carbohydrate (CHO), beverage providing aspartame (APM), and beverage providing APM plus CHO. The APM dose (200 mg) was the amount provided in 12 oz of diet beverage; the CHO was partially hydrolyzed starch (60 g). Plasma amino acid concentrations were determined after dosing and the molar plasma phenylalanine (Phe) to large neutral amino acid (LNAA) ratio calculated. APM administration without CHO did not increase plasma Phe concentrations over baseline values in either normal or PKU subjects (5.48 +/- 0.85 and 150 +/- 23.0 mumols/dL, respectively). Similarly, the Phe/LNAA did not increase significantly. Ingestion of beverage providing APM and CHO did not significantly increase plasma Phe concentrations over baseline values in either normal or PKU subjects. However, ingestion of beverage providing CHO (with or without APM) significantly decreased plasma levels of valine, isoleucine, and leucine 1.5 to 4 hours after dosing in both normal and PKU subjects, thereby increasing the Phe/LNAA ratio significantly. These data indicate that changes noted in Phe/LNAA values after ingestion of beverage providing APM plus CHO were due to CHO. The plasma insulin response to beverage providing CHO (with or without APM) was significantly higher in PKU subjects than in normals.

Repeated ingestion of aspartame-sweetened beverage: effect on plasma amino acid concentrations in individuals heterozygous for phenylketonuria.

It has been suggested that excessive use of aspartame (APM) (N-L-alpha-aspartyl-L-phenylalanine methyl ester) might grossly elevate plasma aspartate and phenylalanine concentrations in individuals heterozygous for phenylketonuria (PKUH). In study 1 six adult PKUH (three males; three females) ingested three successive 12-oz servings of beverage at 2-h intervals. The study was carried out in two parts in a randomized crossover design. In one arm the beverage was not sweetened. In the other the beverage provided 10 mg APM/kg body weight per serving. The addition of APM to the beverage did not significantly increase plasma aspartate concentration but did increase plasma phenylalanine levels 2.3 to 4.1 mumol/dL above baseline values 30 to 45 min after each dose. The high mean plasma phenylalanine level after repeated APM dosing (13.9 +/- 2.15 mumol/dL) was slightly, but not significantly, above the normal postprandial range for PKUH (12.6 +/- 2.11 mumol/dL). In study 2 six different adult PKUH ingested beverage providing 30 mg APM/kg body weight as a single bolus. The high mean plasma phenylalanine concentration and the phenylalanine to large neutral amino acid ratio were significantly higher when APM was ingested as a single bolus than when ingested as a divided dose.

Aspartame-sweetened beverage: effect on plasma amino acid concentrations in normal adults and adults heterozygous for phenylketonuria.

Twelve normal subjects ingested either unsweetened beverage (n = 6) or beverage providing 4 mg/kg body weight as aspartame (APM) (n = 6). Neither beverage had any significant effect on plasma aspartate or phenylalanine concentrations. After this study, eight normal and six obligate phenylketonuric (PKU) heterozygous adults each ingested a 354-mL (12-oz) beverage serving on two occasions in a randomized cross-over design. On one occasion the beverage was not sweetened; on the other occasion, the beverage provided 10 mg APM/kg body weight. Plasma amino acid concentrations were measured throughout the 2-h study period. The addition of 10 mg APM/kg body weight to the beverage had no significant effect on plasma aspartate concentration. APM ingestion increased plasma phenylalanine levels of normal subjects from a mean +/- SD baseline value of 5.09 +/- 0.82 mumol/dL to a high mean value of 6.73 +/- 0.75 mumol/dL. In PKU heterozygous subjects the plasma phenylalanine level increased from a mean +/- SD of 9.04 +/- 1.71 to a high mean value of 12.1 +/- 2.08 mumol/dL. The data indicate ready metabolism of the aspartate and phenylalanine portion of APM when administered at levels likely to be ingested by individuals who drink diet beverages.