Long-term metabolic, endocrine, and neuropsychological outcome of hematopoietic cell transplantation for Wolman disease.

Wolman disease is the infantile form of autosomal recessive acid lipase deficiency, typically presenting in early infancy with diarrhea, massive hepatosplenomegaly, failure to thrive, and calcification of adrenal glands. Hematopoietic cell transplantation (HCT) is the only therapy reported to prevent hepatic failure and death, which without treatment occurs within the first year of life. We report a single institution's experience with HCT treatment of four Wolman patients, two of whom are long-term survivors (the longest survival reported to date, (4 and 11 years). Survivors showed resolution of diarrhea within weeks after engraftment, normalized hepatic function, improved hepatosplenomegaly, and in one patient normal adrenal function. The older patient has normal adaptive functions but mild to moderate neurocognitive deficiencies thought to be secondary to treatment and other medical problems. The younger patient has age-appropriate neurodevelopmental and adaptive abilities. We conclude that Wolman disease can be successfully treated with HCT, and that hepatic and cognitive function can be preserved with early diagnosis and timely referral to a transplant center.

Combination of enzyme replacement and hematopoietic stem cell transplantation as therapy for Hurler syndrome.

Hurler syndrome (mucopolysaccharidosis type I, MPS IH) is characterized by a deficiency of alpha-L-iduronidase resulting in progressive multiorgan dysfunction. We sought to determine whether enzyme replacement therapy (ERT) with iduronidase in the peritransplant period affects outcome of hematopoietic stem cell transplantation (HSCT) for MPS IH. Seven children with MPS IH at a median age of 1.5 years at the time of myeloablative HSCT were eligible. All patients had null mutations in IDUA gene. Iduronidase (0.58 mg/kg per dose) was administered intravenously in 11-14 weekly doses before HSCT and 8 weekly doses after HSCT. The infusions were well tolerated. All patients developed antibodies to iduronidase but all engrafted with >90% donor hematopoiesis. A majority of patients had significant pulmonary complications before ERT and HSCT but all are alive and well with a median follow-up of more than 1 year after HSCT. This suggests that ERT prior to HSCT is unlikely to alter engraftment. In addition, morbidity was acceptable, despite a previous history of pulmonary difficulties that suggested that these patients were high risk for these complications. Therefore, we recommend treatment of MPS IH patients with combination of ERT and HSCT therapy to further investigate its potential to enhance outcomes with HSCT.

N-acetyl-L-cysteine improves outcome of advanced cerebral adrenoleukodystrophy.

Hematopoietic stem cell transplantation as a treatment for childhood cerebral adrenoleukodystrophy (ALD) has historically only been successful in early disease. As ALD is associated with oxidative damage, we reasoned that adjunctive therapy with an antioxidant agent, N-acetyl-L-cysteine (NAC), may provide protection from rapid neurologic decline in boys with advanced cerebral disease. We report three boys with advanced ALD, whose neurologic status and brain radiographic findings were stabilized by treatment including NAC 8-11 months after hematopoietic stem cell transplantation. These results contrast with previous survival data in cerebral ALD patients who had a similar degree of brain involvement, all of whom died within 1 year of stem cell infusion despite a full donor engraftment. Thus, NAC merits investigation as a therapeutic strategy for patients with advanced ALD as an intervention that could change this lethal disease to a condition amendable to treatment with hematopoietic stem cell transplantation.

Assessment of adrenoleukodystrophy lesions by high field MRS in non-sedated pediatric patients.

BACKGROUND: Early detection of white matter lesions in childhood-onset cerebral adrenoleukodystrophy (ALD) is important as hematopoietic cell transplantation (HCT), currently the only effective treatment, is beneficial only if performed early in the disease course. OBJECTIVE: To establish reliable biochemical markers of cerebral disease progression in patients with ALD to aid in treatment planning. METHODS: The authors used proton magnetic resonance spectroscopy (MRS) in combination with LCModel analysis to quantify brain metabolites in small volumes (3 to 16 mL) in the occipital and frontal white matter and the splenium of the corpus callosum of 17 unsedated patients and 26 healthy volunteers (adult n = 21, age-matched n = 5) at 4 tesla. RESULTS: Absolute concentrations of 12 metabolites were reliably determined, seven of which were established as markers of lesion development. Among these, creatine and choline containing compounds were the weakest markers while N-acetylaspartate, glutamine, and lipids + lactate were the strongest. The large extent of changes in the markers enabled detection of early neurochemical changes in lesion formation prior to detection of abnormalities by conventional MRI. Concentrations of a number of metabolites were also significantly different between normal appearing white matter of patients and controls indicating biochemical alterations in the absence of cerebral disease. Neurochemical improvements following HCT were measured in six patients. CONCLUSIONS: The progression of adrenoleukodystrophy, as well as effectiveness of its treatment, can be assessed with high precision using high field 1H magnetic resonance spectroscopy in individual patients without the need for sedation.

Late occurrence of chronic immune-mediated axonal polyneuropathy following bone marrow transplant for juvenile-onset alpha-mannosidosis.

A 23-year-old woman with juvenile-onset alpha-mannosidosis developed an axonal polyneuropathy more than a year following successful unrelated donor (URD) BMT complicated by chronic graft-versus-host disease (GVHD). Progressive muscle weakness and paresthesias developed over at least 4 months, and made her nonambulatory. Nerve conduction and EMG studies demonstrated an axonal sensorimotor neuropathy. Cerebral spinal fluid (CSF) IgG was elevated with two peaks not identified in serum. Strength improved after a single course of plasma exchange and continued to improve over 12 months. The response to plasma exchange, elevated CSF IgG production, and evidence of a serum IgM peak suggest an immune-mediated mechanism. Chronic polyneuropathies following BMT are rare and are usually temporally related to GVHD or infection. This patient's disease was unusual because of its late occurrence and chronic onset in the face of resolved GVHD and in the absence of infection.

Continued neurocognitive development and prevention of cardiopulmonary complications after successful BMT for I-cell disease: a long-term follow-up report.

I-cell disease or mucolipidosis type II, a rare inherited storage disorder of lysosomal enzyme localization, is characterized by dysostosis multiplex, progressive severe psychomotor retardation and death by 5-8 years from congestive heart failure and recurrent pulmonary infections. A 19-month old girl with I-cell disease received a bone marrow transplant (BMT) from an HLA-identical carrier brother. At the age of 7 years, 5 years after BMT, she has no history of respiratory infections. Her cardiac function remains normal with a shortening fraction of 47%, and she continues to gain neurodevelopmental milestones, albeit at a very slow rate. Musculoskeletal deformities have worsened despite BMT. This is the first report describing neurodevelopmental gains and prevention of cardiopulmonary complications in I-cell disease after BMT.

Linkage studies in erythrokeratodermias: fine mapping, genetic heterogeneity and analysis of candidate genes.

Erythrokeratodermias are a clinically heterogeneous group of rare autosomal dominant disorders of cornification with overlapping features including hyperkeratosis and erythema. We ascertained five extended pedigrees with different phenotypes for a linkage study. Three families presented with localized erythrokeratodermia variabilis, and one with erythrokeratodermia and ataxia. Another family had Greither disease associated with variable hyperkeratotic plaques. Despite their phenotypic differences, both erythrokeratodermia variabilis and erythrokeratodermia with ataxia map to a common region in 1p34-p35. Multipoint linkage and haplotype analyses place erythrokeratodermia variabilis between the marker D1S496 and D1S186 with a maximum LOD score of 12.88. Our linkage results provide compelling evidence for genetic homogeneity among families of mixed European and French-Canadian origin. In contrast, results excluded Greither's disease from the established erythrokeratodermia variabilis gene region indicating genetic heterogeneity of erythrokeratodermias. Based on recombinations, two genes assigned to 1p34-p35 were excluded: cartilage matrix protein and avian myelocytosis viral oncogene. Connexin-37 (GJA4), a member of the connexin gene family, maps within the erythrokeratodermia variabilis region and is an attractive candidate gene. Direct sequencing of the coding region of GJA4 in four patients revealed several variations, including a novel polymorphism within the 5' cytoplasmic domain, but no pathogenic mutations were found, thus excluding Connexin-37 as a candidate. There is evidence, however, that other epidermally expressed connexins cluster in this region, and one may yet be determined to play a role in the pathogenesis of erythrokeratodermia variabilis.

Physical mapping and genomic structure of the Lowe syndrome gene OCRL1.

The oculocerebrorenal syndrome of Lowe (OCRL; McKusick 309,000) is a rare X-linked disorder characterized by mental retardation, congenital cataracts, and Fanconi syndrome of the proximal renal tubules. We have carried out physical mapping of the OCRL1 gene and determined that it contains 24 exons occupying 58 kb. The gene, located in Xq25-26, is transcribed in a centromeric to telomeric direction. Primers have been developed that allow all coding exons and their intron/exon boundaries to be amplified from genomic DNA for mutation detection. Two tetranucleotide tandem repeat polymorphisms were characterized that immediately flank the OCRL1 gene and, together, are informative in over 90% of females. Variable splicing was seen in the OCRL1 transcript, involving a small 24-bp exon. These results should prove useful to medical and molecular geneticists studying mutations and providing DNA diagnostic services to families dealing with Lowe syndrome as well as to cell biologists interested in structure-function relationships for the OCRL1 protein.

Evidence for a discrete behavioral phenotype in the oculocerebrorenal syndrome of Lowe.

The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, cognitive impairment, and renal tubular dysfunction. Although there is a wide range of intellectual function in affected individuals, it is often compromised by a high prevalence of maladaptive behaviors, including tantrums, stubborness, and stereotypy. Whether these behaviors simply reflect the multiple disabilities found in some developmentally impaired individuals with or without OCRL, or a specific genetically-determined behavioral phenotype of OCRL, is unknown. Controls were matched for sex, age, visual impairment, and adaptive functioning and compared with OCRL patients on three standardized measures of adaptive/maladaptive behaviors. Forty-three matched pairs of OCRL and control subjects were identified. Both groups were similar in communication, daily living, socialization, and motor skills, in socioeconomic status, and in measures of parental stress. Individuals with OCRL displayed significantly more severe maladaptive behaviors than control boys, as measured by the Vineland Adaptive Behavior Scales (VABS), with 41% of the difference between the two groups attributable to the diagnosis of OCRL. Twelve maladaptive behaviors measured on the VABS appeared more frequently in OCRL than in controls. Five of these 12 behaviors, i.e., temper tantrums, irritability, complex repetitive behaviors (stereotypy)/mannerisms, obsessions/unusual preoccupations, and negativism, were identified by discriminant function analysis to significantly distinguish between controls and OCRL individuals. The diagnosis of OCRL is associated with a behavioral phenotype consisting of temper tantrums, stereotypy, stubborness, and obsessions/unusual preoccupations. This phenotype cannot be attributed solely to the visual, motor, and intellectual disabilities characteristic of OCRL, and may represent a specific effect of the OCRL gene on the central nervous system.

Neurologic profile in osteogenesis imperfecta.

The clinically important neurlogic complications in 76 patients with OI seen at the NIH included brainstem compression from basilar invagination, skull fracture, and seizure disorders. Neuroimaging studies demonstrated sulcal prominence and ventriculomegaly consistent with communicating hydrocephalus in 17 patients. Basilar invagination was found in 8 individuals, all with clinically severe OI, and caused brain-stem compression in 3 patients. Head circumference growth showed abnormal kinetics with percentile crossing after fontanelle closure in 13 patients and absolute macrocephaly was present in 11 patients. Neurologic evaluation should be part of a team approach in the management of patients with severe OI types. Continued study of the underlying pathophysiology of neurologic features in OI is warranted.

Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.

Jackson-Weiss syndrome is an autosomal dominant condition characterized by craniosynostosis, foot anomalies and great phenotypic variability. Recently mutations in fibroblast growth factor receptor 2 (FGFR2) have been found in patients with another craniosynostotic syndrome, Crouzon syndrome. FGFR2 is a member of the tyrosine kinase receptor superfamily, having a high affinity for peptides that signal the transduction pathways for mitogenesis, cellular differentiation and embryogenesis. We now report an FGFR2 mutation in the conserved region of the immunoglobulin IIIc domain in the Jackson-Weiss syndrome family in which the syndrome was originally described. In addition, in four of 12 Crouzon syndrome cases, we identified two new mutations and found two previously described mutations in the same region.

Fetal oculocerebrorenal syndrome of Lowe associated with elevated maternal serum and amniotic fluid alpha-fetoprotein levels.

OBJECTIVE: To report an association between fetal oculocerebrorenal syndrome of Lowe and elevations in maternal serum alpha-fetoprotein (MSAFP) and amniotic fluid alpha-fetoprotein (AFAFP). METHODS: Case 1 was identified during routine MSAFP screening. Cases 2-5 were identified through review of a data base of individuals with oculocerebrorenal syndrome enrolled at the National Institutes of Health. To estimate the frequency of this association, only those whose mothers would have been in the early second trimester from February 1987 to August 1993 were enumerated. The MSAFP was assumed to be normal unless explicitly reported or unless information outside the data base confirmed that MSAFP was not determined. RESULTS: An elevated MSAFP (2.5 multiples of the median [MoM] or greater) was detected in five of 20 pregnancies with a fetus affected by oculocerebrorenal syndrome. Maternal serum alpha-fetoprotein was greater than 5.0 MoM in three pregnancies undergoing amniocentesis, and all had an elevated AFAFP without significant acetylcholinesterase activity. No abnormalities were found by ultrasound, and there was no other cause of elevated AFP identified postnatally. Family history was positive in three of the five cases. The mothers were carriers in four of the five cases, whereas the fifth case appeared to be a spontaneous mutation. CONCLUSIONS: Elevated MSAFP and AFAFP appear to occur at a higher than expected frequency in pregnancies carrying an oculocerebrorenal syndrome fetus. The mechanism of elevation of AFP may be related to fetal renal tubular dysfunction. A directed interview, focusing on a maternal family history of male relatives with unexplained mental retardation, early institutionalization, or congenital rubella, is appropriate with unexplained MSAFP elevations and, particularly, with unexplained AFAFP elevations without acetylcholinesterase activity.

Distal vacuolar myopathy in nephropathic cystinosis.

Nephropathic cystinosis is a lysosomal storage disorder leading to renal failure by age 10 years. Prolonged patient survival following renal transplantation has allowed the development of previously unknown long-term complications. Muscle involvement has been reported in a single posttransplant cystinosis patient, but the range of clinical, electrophysiologic, and histologic features has not been fully described. Thirteen of 54 post-renal-transplant patients that we examined developed weakness and wasting in the small hand muscles, with or without facial weakness and dysphagia. Tendon reflexes were preserved and sensory examinations were normal. Electrophysiologic studies in 11 affected patients showed normal nerve conduction velocities and preserved sensory action potentials. The voluntary motor units in the affected distal muscles had reduced amplitude and brief duration, confirmed with quantitative electromyography in 4 patients. Biopsy of the severely affected abductor digiti minimi or extensor carpi radialis brevis muscles in 2 patients revealed marked fiber size variability, prominent acid phosphatase-positive vacuoles, and absence of fiber type grouping or inflammatory cells. Crystals of cystine were detected in perimysial cells but not within the muscle cell vacuoles. The muscle cystine content of clinically affected muscles was markedly elevated. We conclude that a distal vacuolar myopathy is a common late complication of untreated nephropathic cystinosis. Although the cause is unclear, the general lysosomal defect in this disease may also affect the lysosomes within muscle fibers.

Localization of the 75-kDa inositol polyphosphate-5-phosphatase (INPP5B) to human chromosome band 1p34.

The 75-kDa (type II) inositol polyphosphate-5-phosphatase, originally described in platelets, is one of at least three known enzymes capable of dephosphorylating inositol-1,4,5-trisphosphate (IP3) to inositol-1,4-bisphosphate (IP2). To further characterize these enzymatic forms, we have mapped the gene (INPP5B) coding for the 75-kDa type II enzyme. Using a combination of human x rodent somatic cell hybrids and fluorescence in situ hybridization, we have determined that this gene maps to human chromosome band 1p34.

Communicating hydrocephalus, basilar invagination, and other neurologic features in osteogenesis imperfecta.

Osteogenesis imperfecta (OI) is anecdotally associated with macrocephaly, hydrocephalus, basilar invagination, and cerebral atrophy, but the frequency and the spectrum of neurologic features of this condition are poorly defined. We report our experience with 76 patients with OI seen at NIH. Neuroimaging studies demonstrated sulcal prominence and ventriculomegaly consistent with communicating hydrocephalus in 17 patients. Eight individuals with severe OI types displayed basilar invagination, causing brainstem compression in three patients. Head circumference growth showed abnormal kinetics with percentile crossing after fontanelle closure in 13 patients, and absolute macrocephaly was present in 11 patients. Additional neurologic complications included skull fracture (10 individuals); seizure disorders (five); transient, unexplained long tract signs (three); and spinal compression and pontine, cervical, and thoracic syringohydromyelia (one patient each). The clinically important neurologic complications appear to be brainstem compression from basilar invagination, skull fracture, and seizure disorders. Neurologic evaluation should be part of a team approach in the management of patients with severe OI types.

Muscle carnitine repletion by long-term carnitine supplementation in nephropathic cystinosis.

The renal tubular Fanconi syndrome of children with nephropathic cystinosis causes plasma and muscle carnitine depletion. L-Carnitine replacement therapy for up to 18 mo has previously been shown to normalize plasma but not muscle carnitine levels. We treated six cystinosis patients, aged 1 to 4 y, with a mean dosage of 92 mg L-carnitine/kg/d given every 6 h for an average of 62 mo. Despite fractional excretions of free carnitine ranging from 55 to 108%, plasma-free and total carnitine concentrations were maintained at or above normal levels. At the end of the carnitine replacement period, the six children had muscle-free carnitine values ranging from 16.0 to 28.0 nmol/mg noncollagen protein compared with values of 3.0 to 11.4 for cystinosis children not supplemented with carnitine [normal, 22.7 +/- 5.0 (SD) nmol/mg protein]. Total muscle carnitine values were also normalized by L-carnitine replacement. The monthly increase in total body creatinine production, a measure of muscle mass, was higher (p = 0.036) in children with normal plasma free carnitine concentrations (3.4 +/- 0.9 mg/d) than in children with low plasma free carnitine (2.3 +/- 0.7 mg/d). No serious side effects, such as severe diarrhea, were observed. We conclude that oral L-carnitine replacement can normalize muscle carnitine content in children with cystinosis.

Cognitive and behavioral profile of the oculocerebrorenal syndrome of Lowe.

BACKGROUND: The oculocerebrorenal syndrome of Lowe (OCRL) is an X-linked disorder characterized by congenital cataracts, cognitive impairment, and renal tubular dysfunction. Significant behavioral difficulties have been reported, but no formal study of intelligence or behavior has been described. METHODS: We surveyed IQ and behavior using archival data and standardized instruments in 47 affected males. RESULTS: Mean IQ was in the moderate mental retardation range (40 < or = IQ < or = 54), with 25% of tested individuals in the normal range (IQ > or = 70). The OCRL population was comparable to a normative population with mental retardation in language, communication, and socialization skills, but lower in independent living skills than means of either populations of individuals with mental retardation or visual impairment. Maladaptive behaviors, particularly stubbornness, temper tantrums, and stereotypic behaviors, were very frequent (> 80%). CONCLUSIONS: The diagnosis of OCRL is compatible with normal intelligence. Maladaptive behaviors significantly interfere with adaptive functions. These behaviors appear to define a characteristic behavioral phenotype in OCRL.

Nonsense mutations in the OCRL-1 gene in patients with the oculocerebrorenal syndrome of Lowe.

A candidate gene, OCRL-1, for the oculocerebrorenal syndrome of Lowe (OCRL) has been identified via positional cloning strategies. We have now developed RT-PCR techniques which allow amplification of nearly all of the open reading frame from total RNA and have used the PCR products for mutational analysis. Single strand conformational polymorphism analysis detected aberrant migration in two unrelated patients, both of whom were shown to have the same nonsense mutation at base 2746 on direct sequencing. An additional patient was found to be missing a segment from his RNA that corresponds to an entire exon. The identification of mutations in the OCRL-1 gene provides strong genetic evidence for its being the gene involved in Lowe syndrome.