Treatment of severe osteoporosis with alendronate in a patient with lysinuric protein intolerance

Lysinuric protein intolerance (LPI) is a rare autosomal inherited disease caused by defective cationic aminoacid transport 4F2hc/y þ LAT-1 at the basolateral membrane of epithelial cells in the intestine and kidney. LPI is a multisystemic disease with a variety of clinical symptoms such as hepatosplenomegaly, osteoporosis, hypotonia, developmental delay, pulmonary insufficiency or end-stage renal disease. The SLC7A7 gene, which encodes the y þ LAT-1 protein, is mutated in LPI patients. Mutation analysis of the promoter localized in intron 1 and all exons of the SLC7A7 gene was performed in 11 patients from 9 unrelated LPI families. Point mutation screening was performed by exon direct sequencing and a new multiplex ligation probe amplification (MLPA) assay was set up for large rearrangement analysis. Eleven SLC7A7-specific mutations were identified, seven of them were novel: p.L124P, p.C425R, p.R468X, p.Y274fsX21, c.625 þ 1G4C, DelE4-E11 and DelE6-E11. The novel large deletions originated by the recombination of Alu repeats at introns 3 and 5, respectively, with the same AluY sequence localized at the SLC7A7 3 0 region. The novel MLPA assay is robust and valuable for LPI molecular diagnosis. Our results suggest that genomic rearrangements of SLC7A7 play a more important role in LPI than has been reported, increasing the detection rate from 5.1 to 21.4%. Moreover, the 3 0 region AluY repeat could be a recombination hot spot as it is involved in 38% of all SLC7A7 rearranged chromosomes described so far.

show abstract

“…All patients are under treatment with L-citrulline (treatment of patient no. 2 has been already reported 22 ).…”

Section: Clinical Datamentioning

confidence: 58%

Novel SLC7A7 large rearrangements in lysinuric protein intolerance patients involving the same AluY repeat

et al. 2008

View full text Add to dashboard Cite

show abstract

“…Therapy with alendronate has been proposed for osteoporosis in LPI [Gomez et al, 2006], but oral therapy is not standardized and this option should be carefully considered to avoid side effects. Severe delay of linear growth is not rare in LPI and can be associated with growth hormone deficiency [Esposito et al, 2006].…”

Section: Therapymentioning

confidence: 99%

Lysinuric protein intolerance: Reviewing concepts on a multisystem disease

Sebastio

Sperandeo

Andria³

2011

American J of Med Genetics Pt C

107

View full text Add to dashboard Cite

Lysinuric protein intolerance (LPI) is an inherited aminoaciduria caused by defective cationic amino acid transport at the basolateral membrane of epithelial cells in intestine and kidney. LPI is caused by mutations in the SLC7A7 gene, which encodes the y(+)LAT-1 protein, the catalytic light chain subunit of a complex belonging to the heterodimeric amino acid transporter family. LPI was initially described in Finland, but has worldwide distribution. Typically, symptoms begin after weaning with refusal of feeding, vomiting, and consequent failure to thrive. Hepatosplenomegaly, hematological anomalies, neurological involvement, including hyperammonemic coma are recurrent clinical features. Two major complications, pulmonary alveolar proteinosis and renal disease are increasingly observed in LPI patients. There is extreme variability in the clinical presentation even within individual families, frequently leading to misdiagnosis or delayed diagnosis. This condition is diagnosed by urine amino acids, showing markedly elevated excretion of lysine and other dibasic amino acids despite low plasma levels of lysine, ornithine, and arginine. The biochemical diagnosis can be uncertain, requiring confirmation by DNA testing. So far, approximately 50 different mutations have been identified in the SLC7A7 gene in a group of 142 patients from 110 independent families. No genotype-phenotype correlation could be established. Therapy requires a low protein diet, low-dose citrulline supplementation, nitrogen-scavenging compounds to prevent hyperammonemia, lysine, and carnitine supplements. Supportive therapy is available for most complications with bronchoalveolar lavage being necessary for alveolar proteinosis.

show abstract

“…Bone density was not assessed in a trial of oral lysine supplementation [16] . There is a single report of the use of alendronate in an 11-year-old female with LPI, with improvement in bone density after one year of therapy [17] . Zoledronic acid was started in our patient prior to his diagnosis of LPI, and within the first year of therapy, decreased fracture frequency was noted.…”

Section: Discussionmentioning

confidence: 99%

Lysinuric protein intolerance presenting with multiple fractures

Posey

Burrage

Miller

et al. 2014

Molecular Genetics and Metabolism Reports

View full text Add to dashboard Cite

Lysinuric protein intolerance (LPI) is a rare autosomal recessive inborn error of metabolism caused by mutations in SLC7A7, which encodes a component of the dibasic amino acid transporter found in intestinal and renal tubular cells. Patients typically present with vomiting, diarrhea, irritability, failure to thrive, and symptomatic hyperammonemia after protein-rich meals. Long-term complications may include pulmonary alveolar proteinosis, renal disease, and osteoporosis. We present a 5-year-old male who was followed in our skeletal dysplasia clinic for 3 years for multiple fractures, idiopathic osteoporosis, and short stature in the absence of typical features of LPI. Whole exome sequencing performed to determine the etiology of the osteoporosis and speech delay identified a nonsense mutation in SLC7A7. Chromosome microarray analysis identified a deletion involving the second allele of the same gene, and biochemical analysis supported the diagnosis of LPI. Our patient's atypical presentation underscores the importance of maintaining a high index of suspicion for LPI in patients with unexplained fractures and idiopathic osteoporosis, even in the absence of clinical symptoms of hyperammonemia after protein rich meals or other systemic features of classical LPI. This case further demonstrates the utility of whole exome sequencing in diagnosis of unusual presentations of rare disorders for which early intervention may modify the clinical course.

show abstract

Treatment of severe osteoporosis with alendronate in a patient with lysinuric protein intolerance

Abstract: Lysinuric protein intolerance is an inborn error of cationic amino acid transport of which osteoporosis is a major feature. Treatment with oral bisphosphonates improves bone mineral density even in severe osteoporosis.

Cited by 12 publications

References 3 publications

Novel SLC7A7 large rearrangements in lysinuric protein intolerance patients involving the same AluY repeat

Novel SLC7A7 large rearrangements in lysinuric protein intolerance patients involving the same AluY repeat

Lysinuric protein intolerance: Reviewing concepts on a multisystem disease

Lysinuric protein intolerance presenting with multiple fractures

Contact Info

Product

Resources

About