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Biomedical subjects

P S Kishnani

Publications and source records attributed to P S Kishnani.

17 recordsLinked to original sources
PubMed2006

Recombinant human acid [alpha]-glucosidase: major clinical benefits in infantile-onset Pompe disease.

BACKGROUND: Pompe disease is a progressive metabolic neuromuscular disorder resulting from deficiency of lysosomal acid alpha-glucosidase (GAA). Infantile-onset Pompe disease is characterized by cardiomyopathy, respiratory and skeletal muscle weakness, and early death. The safety and efficacy of recombinant human (rh) GAA were evaluated in 18 patients with rapidly progressing infantile-onset Pompe disease. METHODS: Patients were diagnosed at 6 months of age and younger and exhibited severe GAA deficiency and cardiomyopathy. Patients received IV infusions of rhGAA at 20 mg/kg (n = 9) or 40 mg/kg (n = 9) every other week. Analyses were performed 52 weeks after the last patient was randomized to treatment. RESULTS: All patients (100%) survived to 18 months of age. A Cox proportional hazards analysis demonstrated that treatment reduced the risk of death by 99%, reduced the risk of death or invasive ventilation by 92%, and reduced the risk of death or any type of ventilation by 88%, as compared to an untreated historical control group. There was no clear advantage of the 40-mg/kg dose with regard to efficacy. Eleven of the 18 patients experienced 164 infusion-associated reactions; all were mild or moderate in intensity. CONCLUSIONS: Recombinant human acid alpha-glucosidase is safe and effective for treatment of infantile-onset Pompe disease. Eleven patients experienced adverse events related to treatment, but none discontinued. The young age at which these patients initiated therapy may have contributed to their improved response compared to previous trials with recombinant human acid alpha-glucosidase in which patients were older.

Dose-Response Relationship, Drug↗
PubMed2005

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.

Adolescent↗
PubMed2005

Hepatocellular carcinoma in glycogen storage disease type Ia: a case series.

We present a series of 8 patients (6 males, 2 females) with hepatocellular carcinoma (HCC) and glycogen storage disease type Ia (GSD Ia). In this group, the age at which treatment was initiated ranged from birth to 39 years (mean 9.9 years). All patients but one were noncompliant with treatment. Hepatic masses were first detected at an age range of 13-45 years (mean 28.1 years). Age at diagnosis of HCC ranged from 19 to 49 years (mean 36.9 years). Duration between the diagnosis of liver adenomas and the diagnosis of HCC ranged from 0 to 28 years (mean 8.8 years, SD = 11.5). Two patients had positive hepatitis serologies (one hepatitis B, one hepatitis C). Alpha-fetoprotein (AFP) was normal in 6 of the 8 patients. Carcinoembryonic antigen (CEA) was normal in the 5 patients in which it was measured. Current guidelines recommend abdominal ultrasonography with AFP and CEA levels every 3 months once patients develop hepatic lesions. Abdominal CT or MRI is advised when the lesions are large or poorly defined or are growing larger. We question the reliability of AFP and CEA as markers for HCC in GSD Ia. Aggressive interventional management of masses with rapid growth or poorly defined margins may be necessary to prevent the development of HCC in this patient population.

Adenoma↗
PubMed2005

Divergent phenotypes in Gaucher disease implicate the role of modifiers.

BACKGROUND: Gaucher disease is classified into neuronopathic and non-neuronopathic forms with wide phenotypic variation among patients sharing the same genotype. While homozygosity for the common L444P allele usually correlates with the neuronopathic forms, how a defined genotype leads to a phenotype remains unknown. METHODS: The genetic and epigenetic factors causing phenotypic differences were approached by a clinical association study in 32 children homozygous for the point mutation L444P. Direct sequencing and Southern blots were utilised to establish the genotype and exclude recombinant alleles. Glucocerebrosidase activity was measured in lymphoblast and fibroblast cell lines. RESULTS: Residual enzyme activity was highly variable and did not correlate with the observed clinical course. There was also a wide spectrum of phenotypes. Average age at diagnosis was 15 months, and slowed saccadic eye movements were the most prevalent finding. The most severe systemic complications and highest mortality occurred in splenectomised patients before the advent of enzyme replacement therapy (ERT). On ERT, as morbidity and mortality decreased, developmental and language deficits emerged as a major issue. Some trends related to ethnic background were observed. CONCLUSION: The wide clinical spectrum observed in the L444P homozygotes implicates the contribution of genetic modifiers in defining the phenotype in Gaucher disease.

Child, Preschool↗
PubMed2003

Evaluation of 3-methylcrotonyl-CoA carboxylase deficiency detected by tandem mass spectrometry newborn screening.

Since the addition of tandem mass spectrometry (MS/MS) to the North Carolina Newborn Screening Program, 20 infants with two consecutive elevated 3-hydroxyisovalerylcarnitine (C5OH) levels have been evaluated for evidence of inborn errors of metabolism associated with this metabolite. Ten of these 20 infants had significant concentrations of both 3-hydroxyisovaleric acid and 3-methylcrotonylglycine in their urine, suggestive of 3-methylcrotonyl-CoA carboxylase (3-MCC) deficiency. Four of these 10 were infants whose abnormal metabolites were found to be of maternal origin. Of 8 patients with probable 3-MCC deficiency, 7 have been tested and found to have the enzyme deficiency confirmed in lymphoblasts or cultured fibroblasts; one of these 7 infants had only marginally decreased 3-MCC activity in lymphocytes but deficient 3-MCC in fibroblasts. We estimate the incidence of 3-MCC deficiency at 1:64000 live births in North Carolina. We conclude that MS/MS newborn screening will detect additional inborn errors of metabolism, such as 3-MCC deficiency, not traditionally associated with newborn screening. The evaluation of newborns with two abnormally elevated C5OH levels on MS/MS newborn screening should include, at least, urine organic acid analysis by capillary GC-MS and a plasma acylcarnitine profile by MS/MS. Long-term follow-up is needed to determine the outcome of presymptomatically diagnosed patients with 3-MCC deficiency by MS/MS newborn screening.

Acids↗
PubMed2001

Frequency of celiac disease in individuals with Down syndrome in the United States.

Ninety-three individuals with Down syndrome (DS) were screened to investigate the prevalence of celiac disease (CD) in the United States. Five of the 93 individuals were antiendomysial antibody (EMA) positive. Of the 5 who tested positive for EMA, 4 were biopsied, 1 refused biopsy. Three of the 4 individuals biopsied manifested changes of CD on small bowel biopsy. This gives a frequency of 3.2% of confirmed CD in our DS individuals and suggests the need for periodic screening for celiac disease in this population.

Adolescent↗
PubMed2001

Canine model and genomic structural organization of glycogen storage disease type Ia (GSD Ia).

A canine model of glycogen storage disease Ia (GSD Ia), similar clinically, biochemically, and pathologically to the human disease, was established by crossbreeding Maltese and Beagle dogs carrying a mutated, defective glucose-6-phosphatase (G-6-Pase) gene. Ten puppies were born in three litters from these crossbreedings. Six were homozygous for the previously described M121I GSD Ia mutation. Of these six affecteds, two were stillborn, and one died at 2, 32, and 60 days of life, respectively (puppies A, B, C, D, E), while one is alive at age 15 months (puppy F). Affected puppies exhibited tremors, weakness, and neurologic signs when hypoglycemic. They had postnatal growth retardation and progressive hepatomegaly. Biochemical abnormalities included fasting hypoglycemia, hyperlactacidemia, hypercholesterolemia, hypertriglyceridemia, and hyperuricemia. Microscopic examination of tissues from affected puppies showed diffuse, marked hepatocellular vacuolation, with distended clear hepatocytes and central to marginally located rounded nuclei. In the kidneys of puppies D and E, there was segmental glomerular sclerosis and vacuolation of proximal convoluted tubular epithelium. Biochemical analysis revealed increased liver glycogen content and isolated markedly reduced G-6-Pase enzyme activity in liver and kidney. The canine G-6-Pase gene was characterized by screening a canine genomic library. It spans approximately 11.8 kb and consists of five exons with >90% amino acid sequence homology to the derived human sequence. The first 1.5 kb of the 5' region was sequenced and contains several putative response element motifs homologous to the human 5' region. Establishment of this canine colony of GSD Ia that closely resembles human disease and isolation of the canine genomic gene provides an excellent model for studying pathophysiology and long-term complications and an opportunity to develop novel therapeutic approaches such as drug and gene therapy.

Animals↗
PubMed2000

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.

Acute Disease↗
PubMed2000

Genotype-phenotype correlation in two frequent mutations and mutation update in type III glycogen storage disease.

Deficiency of glycogen debranching enzyme (AGL) activity causes glycogen storage disease type III (GSD-III). Generalized loss of AGL activity results in GSD-IIIa, and muscle-specific retention of AGL activity results in GSD-IIIb. To date, no common mutation has been described among GSD-III patients, except for three alleles; two linked specifically with GSD-IIIb, and the third found only in North African Jews with GSD-IIIa. Here we report two frequent mutations, each of which was found in the homozygous state in multiple patients, and each of which was associated with a subset of clinical phenotype in those patients with that mutation. A novel point mutation of a single T deletion at cDNA position 3964 (3964delT) was first detected in an African American patient, who has a severe phenotype and early onset of clinical symptoms. The second mutation was an A to G transition at position -12 upstream of the 3' splice site of intron 32 (IVS32-12A > G). This lesion, previously implicated as a IIIb mutation in a Japanese patient, was identified in a confirmed GSD-IIIa Caucasian patient presenting with mild clinical symptoms. These two mutations together account for more than 12% of the molecular defects in the GSD-III patients tested. Our molecular and clinical data suggest a genotype-phenotype correlation for each of these mutations. Furthermore, this current study, coupled with our previous reports, describes the molecular tools necessary for the development of a DNA-based diagnostic test for GSD-III.

Adult↗
PubMed1999

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.

Amino Acids↗
PubMed1999

Nutritional deficiencies in a patient with glycogen storage disease type Ib.

The current mainstay of treatment in glycogen storage disease type I (GSD I) is dietary management that includes providing a frequent source of glucose to prevent hypoglycaemia. To ensure compliance, routine follow-up by a health care team, including a dietitian, experienced in the treatment of GSD is necessary. We describe an adolescent patient with GSD Ib in good metabolic control who was admitted with a 3-month history of weakness, depression, vomiting, decreased appetite and a 11.4-kg weight loss. He had a recent onset of unsteady gait, inability to write, and sore mouth. After an extensive work-up, the patient was found to have vitamin B12, folate, iron and other nutritional deficiencies, which explained his symptoms. The patient improved within 72 h of initiation of total parenteral nutrition and therapeutic doses of deficient micronutrients, with a complete recovery in 2 months. Dietary restrictions, dependence on non-food products (e.g. cornstarch in GSD I), and social and developmental issues place individuals with metabolic disorders at a high risk for developing an array of nutritional deficiencies. This case highlights the importance of both close follow-up of the metabolic control and close monitoring of growth and nutritional intake in individuals with inborn errors of metabolism. This case also illustrates the importance of daily supplementation with appropriate multivitamins, calcium and other minerals needed to meet the Recommended Dietary Allowances (RDAs) in these patients.

Adolescent↗
PubMed1997

Isolation and nucleotide sequence of canine glucose-6-phosphatase mRNA: identification of mutation in puppies with glycogen storage disease type Ia.

Two Maltese puppies with massive hepatomegaly and failure to thrive had isolated deficient glucose-6-phosphatase (G-6-Pase) activity in liver and kidney and pathological findings compatible with GSD-Ia. To identify the mutation, we cloned G-6-Pase canine cDNA by RT-PCR with primers from the murine G-6-Pase gene sequence. The canine G-6-Pase cDNA is 2346 bp, with a 5' untranslated region of 87 bp, a coding region of 1071 bp, and a 3' untranslated region of 1185 bp. The difference between the canine and human sequences is in the 3' untranslated region. A greater than 90% amino acid sequence homology was seen with canine, human, murine, and rat G-6-Pase. G-6-Pase cDNA from affected and control puppies revealed complete homology except at nt position 450, which showed a guanine to cytosine (G to C) transversion resulting in substitution of a methionine by isoleucine at codon 121 (M121I) in all five clones studied. The loss of an NcoI restriction site on genomic DNA amplified with primers flanking the mutation allowed us to prove that affected puppies were homozygous for the mutation and parents were heterozygous carriers. The mutant G-6-Pase cDNA had 15 times less enzyme activity than wild-type cDNA following transient transfection. Northern blot analysis of puppies with GSD-Ia revealed increased G-6-Pase mRNA, compared to normal controls. Increased G-6-Pase mRNA was also seen in normal fasted puppies compared to littermates in the fed state, suggesting that the increased G-6-Pase mRNA is a physiologic response to fasting. This is the first report of a molecularly confirmed naturally occurring animal model of GSD-Ia. The establishment of a breeding colony of this dog strain will facilitate studies on the role of G-6-Pase gene in glucose homeostasis, in pathophysiology of disease, and development of novel therapeutic approaches such as gene therapy.

Amino Acid Sequence↗
PubMed1996

Acute pancreatitis in an infant with lactic acidosis and a mutation at nucleotide 3243 in the mitochondrial DNA tRNALeu(UUR) gene.

UNLABELLED: The A to G point mutation at position 3243 of the mitochondrial DNA tRNALeu(UUR) gene is commonly found in patients with the syndrome of mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). A male patient was referred at 7 months with failure to thrive, developmental delay, microcephaly and hypotonia since age 2 months. He had developed lactic acidosis and increasingly frequent seizures since age 5 months. The patient was admitted at 15 months with pleural and pericardial effusions, which resolved. Three weeks later he developed evidence of pancreatitis with hyperglycemia, sudden profound increase in lactic acidosis and increased serum lipase. He died unexpectedly the next day of cardiorespiratory collapse following an acute gastro-intestinal hemorrhage. Analysis of mitochondrial DNA (mtDNA) in muscle showed heteroplasmy for the mutation MTTL1*MELAS3243G (> 95%). Infants with this mutation commonly present with failure to thrive, significant developmental delay, and hypotonia, while stroke-like episodes occur later in survivors. They usually have lactic acidosis and a high percentage of mutant mtDNA in muscle. CONCLUSION: Respiratory chain disorders including the mtDNA MTTL1*MELAS3243G mutation should be suspected in infants with this systemic and neurologic presentation. Pancreatic dysfunction, both acute and chronic, needs to be added to the list of symptoms of disorders of the respiratory chain.

Acidosis, Lactic↗